Papers with high citation statistics associated with NYSBC investigators

NMR/ Structural Biology

Title: Structure and ligand of a histone acetyltransferase bromodomain ( #49 , Mar 08, #64 of >20,000 related Oct 2005)

Author(s): Dhalluin C, Carlson JE, Zeng L, He C, AneelAggarwal, MingMingZhou Source: NATURE 399 (6735): 491-496 JUN 3 1999

Abstract: Histone acetylation is important in chromatin remodelling and gene activation(1-4). Nearly all known histone-acetyltransferase (HAT)-associated transcriptional co-activators contain bromodomains, which are similar to 110-amino-acid modules found in many chromatin-associated proteins(5-9). Despite the wide occurrence of these bromodomains, their three-dimensional structure and binding partners remain unknown. Here we report the solution structure of the bromodomain of the HAT co-activator P/CAF (p300/CBP-associated factor)(10,11). The structure reveals an unusual left-handed up-and-down four-helix bundle. In addition, we show by a combination of structural and site-directed mutagenesis studies that bromodomains can interact specifically with acetylated lysine, making them the first known protein modules to do so, The nature of the recognition of acetyl-lysine by the P/CAF bromodomain is similar to that of acetyl-CoA by histone acetyltransferase. Thus, the bromodomain is functionally linked to the HAT activity of co-activators in the regulation of gene transcription.

Title: MOLECULAR-BASIS OF HUMAN 46X,Y SEX REVERSAL REVEALED FROM THE 3-DIMENSIONAL SOLUTION STRUCTURE OF THE HUMAN SRY-DNA COMPLEX (#69 of > 20000 Oct 2005)

Source: CELL 81 (5): 705-714 JUN 2 1995

Cited References: 49 Times Cited: 293

Abstract: The solution structure of the specific complex between the high mobility group (HMG) domain of SRY (hSRY-HMG), the protein encoded by the human testis-determining gene, and its DNA target site in the promoter of the Mullerian inhibitory substance gene has been determined by multidimensional NMR spectroscopy. hSRY-HMG has a twisted L shape that presents a concave surface (made up of three helices and the N- and C-terminal strands) to the DNA for sequence-specific recognition. Binding of hSRY-HMG to its specific target site occurs exclusively in the minor groove and induces a large conformational change in the DNA. The DNA in the complex has an overall 70 degrees-80 degrees bend and is helically unwound relative to classical A- and B-DNA. The structure of the complex reveals the origin of sequence-specific binding within the HMG-1/HMG-2 family and provides a framework for understanding the effects of point mutations that cause 46X, Y sex reversal at the atomic level.

Title: Modular peptide recognition domains in eukaryotic signaling (review, #106, Mar 08; #98 of > 20000 Oct 2005)

Source: ANNUAL REVIEW OF BIOPHYSICS AND BIOMOLECULAR STRUCTURE 26: 259-288 1997

Cited References: 104 Times Cited: 239

Abstract: A characteristic feature of cellular signal transduction pathways in eukaryotes is the separation of catalysis from target recognition. Several modular domains that recognize short peptide sequences and target signaling proteins to these sequences have been identified. The structural bases of the specificities of recognition by SH2, SH3, and PTB domains have been elucidated by X-ray crystallography and NMR, and these results are reviewed here. In addition, the mechanism of cooperative interactions between these domains is discussed.

176. Title: Nuclear magnetic resonance methods for quantifying microsecond-to-millisecond motions in biological macromolecules Mar 08

Title: Structural changes linked to proton translocation by subunit c of the ATP synthase (#195 of > 20000 Oct 05)

Source: NATURE 402 (6759): 263-268 NOV 18 1999

Cited References: 50 Times Cited: 179

Abstract: F1F0 ATP synthases use a transmembrane proton gradient to drive the synthesis of cellular ATP. The structure of the cytosolic F-1 portion of the enzyme and the basic mechanism of ATP hydrolysis by F-1 are now well established, but how proton translocation through the transmembrane F-0 portion drives these catalytic changes is less clear. Here we describe the structural changes in the proton-translocating F-0 subunit c that are induced by deprotonating the specific aspartic acid involved in proton transport. conformational changes between the protonated and deprotonated forms of subunit c provide the structural basis for an explicit mechanism to explain coupling of proton translocation by F-0 to the rotation of subunits within the core of F-1. Rotation of these subunits within F-1 causes the catalytic conformational changes in the active sites of F-1 that result in ATP synthesis.

Source: STRUCTURE 1 (4): 263-282 DEC 15 1993

Cited References: 55 Times Cited: 179

Abstract: Background: Repeats of G, sequences are detected as single strand overhangs at the ends of eukaryotic chromosomes together with associated binding proteins. Such telomere sequences have been implicated in the replication and maintenance of chromosomal termini. They may also mediate chromosomal organization and association during meiosis and mitosis.

Results: We have determined the three-dimensional solution structure of the human telomere sequence, d[AG(3)(T(2)AG(3))(3)] in Na+-containing solution using a combined NMR, distance geometry and molecular dynamics approach (including relaxation matrix refinement). The sequence, which contains four AG(3) repeats, folds intramolecularly into a G-tetraplex stabilized by three stacked G-tetrads which are connected by two lateral loops and a central diagonal loop. Of the four grooves chat are formed, one is wide, two are of medium width and one is narrow. The alignment of adjacent G-G-G segments in parallel generates the two grooves of medium width whilst the antiparallel arrangement results in one wide and one narrow groove. Three of the four adenines stack on top of adjacent G-tetrads while the majority of the thymines sample multiple conformations.

Conclusions: The availability of the d[AG(3)(T(2)AG(3))(3)] solution structure containing four AG(3) human telomeric repeats should permit the rational design of ligands that recognize and bind with specificity and affinity to the individual grooves of the G-tetraplex, as well as to either end containing the diagonal and lateral loops. Such ligands could modulate the equilibrium between folded G-tetraplex structures and their unfolded extended counterparts.

Title: Solution structure of the proapoptotic molecule BID: A structural basis for apoptotic agonists and antagonists ( #217, Mar 08 , #226 of > 20000 Oct 05)

Author(s): McDonnell JM, Fushman D, Milliman CL, Korsmeyer SJ, Cowburn D

Source: CELL 96 (5): 625-634 MAR 5 1999

Cited References: 66 Times Cited: 169

Abstract: Members of the BCL2 family of proteins are key regulators of programmed cell death, acting either as apoptotic agonists or antagonists. Here we describe the solution structure of BID, presenting the structure of a proapoptotic BCL2 family member. An analysis of sequence/structure of BCL2 family members allows us to define a structural superfamily, which has implications for general mechanisms for regulating proapoptotic activity. It appears two criteria must be met for proapoptotic function within the BCL2 family: targeting of molecules to intracellular membranes, and exposure of the BH3 death domain. BID's activity is regulated by a Caspase 8-mediated cleavage event, exposing the BH3 domain and significantly changing the surface charge and hydrophobicity, resulting in a change of cellular localization.

Title: Nuclear magnetic resonance studies of biopolymer dynamics (#235 of > 20000 Oct 05)

Source: JOURNAL OF PHYSICAL CHEMISTRY 100 (31): 13293-13310 AUG 1 1996

Cited References: 190 Times Cited: 166

Abstract: NMR spectroscopy is a powerful approach for quantitating molecular conformational dynamics at multiple atomic sites and over multiple time scales. Extensive studies by solution and solid-state NMR spectroscopy of spin relaxation and line shapes in biological macromolecules have been performed in order to characterize the amplitudes, time scales, and energetics of intramolecular conformational modes and to elucidate the relationships between conformational dynamics, structure, and function. This review describes NMR spectroscopic methods for investigation of conformational dynamics together with theoretical descriptions appropriate for interpretation and simulation of the techniques, surveys the range of results available from solution and solid state NMR studies of proteins and other biomolecules, and identifies opportunities for further individual and collaborative development of solution and solid state NMR techniques for characterizing the dynamical properties of biological macromolecules.

Title: BACKBONE DYNAMICS OF CALCIUM-LOADED CALBINDIN-D(9K) STUDIED BY 2-DIMENSIONAL PROTON-DETECTED N-15 NMR-SPECTROSCOPY (#292 of > 20000 Oct 05)

Source: BIOCHEMISTRY 31 (20): 4856-4866 MAY 26 1992

Cited References: 67 Times Cited: 162

Abstract: Backbone dynamics of calcium-loaded calbindin D9k have been investigated by two-dimensional proton-detected heteronuclear nuclear magnetic resonance spectroscopy, using a uniformly N-15 enriched protein sample. Spin-lattice relaxation rate constants, spin-spin relaxation rate constants, and steady-state {H-1}-N-15 nuclear Overhauser effects were determined for 71 of the 72 backbone amide N-15 nuclei. The relaxation parameters were analyzed using a model-free formalism that incorporates the overall rotational correlation time of the molecule, and a generalized order parameter (S2) and an effective internal correlation time for each amide group. Calbindin D9k contains two helix-loop-helix motifs joined by a linker loop at one end of the protein and a beta-type interaction between the two calcium-binding loops at the other end. The amplitude of motions for the calcium-binding loops and the helices are similar, as judged from the average S2 values of 0.83 +/- 0.05 and 0.85 +/- 0.04, respectively. The linker region joining the two calcium-binding subdomains of the molecule has a significantly higher flexibility, as indicated by a substantially lower average S2 value of 0.59 +/- 0.23. For residues in the linker loop and at the C-terminus, the order parameter is further decomposed into separate order parameters for motional processes on two distinct time scales. The effective correlation times are significantly longer for helices I and IV than for helices II and III or for the calcium-binding loops. Residue by residue comparisons reveal correlations of the order parameters with both the crystallographic B-factors and amide proton exchange rates, despite vast differences in the time scales to which these properties are sensitive. The order parameters are also utilized to distinguish regions of the NMR-derived three-dimensional structure of calbindin D9k that are poorly defined due to inherently high flexibility, from poorly defined regions with average flexibility but a low density of structural constraints.

Title: PROTEIN DYNAMICS STUDIED BY ROTATING FRAME N-15 SPIN RELAXATION-TIMES (#276 of 20000, Oct 05)

Source: JOURNAL OF BIOMOLECULAR NMR 3 (2): 151-164 MAR 1993

Cited References: 48 Times Cited: 153

Abstract: Conformational rate processes in aqueous solutions of uniformly N-15-labeled pancreatic trypsin inhibitor (BPTI) at 36-degrees-C were investigated by measuring the rotating frame relaxation times of the backbone N-15 spins as a function of the spin-lock power, Two different intramolecular exchange processes were identified. A first local rate process involved the residues Cys38 and Arg39, had a correlation time of about 1.3 ms, and was related to isomerization of the chirality of the disulfide bond Cys14-Cys38. A second, faster motional mode was superimposed on the disulfide bond isomerization and was tentatively attributed to local segmental motions in the polypeptide sequence - Cys14 - Ala15 - Lys16 -. The correlation time for the overall rotational tumbling of the protein was found to be 2 ns, using the assumption that relaxation is dominated by dipolar coupling and chemical shift anistropy modulated by isotropic molecular reorientation.

Title: Solution structure of the transmembrane H+-transporting subunit c of the F1F0 ATP synthase (#283 of >20000 Oct 05)

Source: BIOCHEMISTRY 37 (25): 8817-8824 JUN 23 1998

Cited References: 56 Times Cited: 151

Abstract: Subunit c is the H+-translocating component of the F1F0 ATP synthase complex. H+ transport is coupled to conformational changes that ultimately lead to ATP synthesis by the enzyme. The properties of the monomeric subunit in a single phase solution of chloroform-methanol - water (4:4:1) have been shown to mimic those of the protein in the native complex. Triple resonance NMR experiments were used to determine the complete structure of monomeric subunit c in this solvent mixture. The structure of the protein was defined by >2000 interproton distances, 64 (3)J(N alpha), and 43 hydrogen-bonding NMR-derived restraints. The root mean squared deviation for the backbone atoms of the two transmembrane helices was 0.63 Angstrom. The protein folds as a hairpin of two antiparallel helical segments, connected by a short structured loop. The conserved Arg41-Gln42-Pro43 form the top of this loop. The essential H+-transporting Asp61 residue is located at a slight break in the middle of the C-terminal helix, just prior to Pro64. The C-terminal helix changes direction by 30 +/- 5 degrees at the conserved Pro64. In its protonated form, the Asp61 lies in a cavity created by the absence of side chains at Gly23 and Gly27 in the N-terminal helix. The shape and charge distribution of the molecular surface of the monomeric protein suggest a packing arrangement for the oligomeric protein in the F-o complex, with the front face of one monomer packing favorably against the back face of a second monomer. The packing suggests that the proton (cation) binding site lies between packed pairs of adjacent subunit c.

NMR / Related techniques

Title: INTRAMOLECULAR MOTIONS OF A ZINC FINGER DNA-BINDING DOMAIN FROM XFIN CHARACTERIZED BY PROTON-DETECTED NATURAL ABUNDANCE C-12 HETERONUCLEAR NMR-SPECTROSCOPY (#28)

Source: JOURNAL OF THE AMERICAN CHEMICAL SOCIETY 113 (12): 4371-4380 JUN 5 1991

Cited References: 91 Times Cited: 384

Abstract: The zinc finger DNA-binding domain Xfin-31 is a 25-residue peptide that binds a single zinc atom and forms a compact globular structure in solution. To characterize the intramolecular dynamics of Xfin-31, the C-13 spin-lattice and spin-spin relaxation rate constants and the {H-1}-C-13 nuclear Overhauser effect (NOE) enhancements have been measured for the backbone and side chain methine carbons by two-dimensional proton-detected heteronuclear NMR spectroscopy at a C-13 Larmor frequency of 125 MHz and natural C-13 abundance. The relaxation rate constants and the NOE enhancements have been analyzed by using a model-free formalism that depends on the overall rotational correlation time of the molecule, tau-m, the order parameter S, and effective internal correlation time, tau-e, for each methine carbon. The optimized global value of tau-m is 1.88 +/- 0.02 ns. The backbone C-alpha carbons are grouped into four categories based on the values of the order parameters: the N-terminal residue Tyr1 with S2 = 0.73 +/- 0.04; the C-terminal residues Lys24 and Asn25 with S2 < 0.5; residues Phe10-Lysl3 with an average S2 = 0.77 +/- 0.03; and the remainder of the backbone carbon nuclei with an average S2 = 0.89 +/- 0.05. For the side chain C-beta of Val11 and Val22 and the C-gamma of Leu5, the values of S2 are 0.62 +/- 0.03, 0.66 +/- 0.04, and 0.47 +/- 0.03, respectively. Estimates of tau-e could be obtained for 13 of the backbone and 3 of the side chain methine carbons. Excluding the terminal residues, the average value of tau-e for the backbone carbon nuclei was 34 +/- 16 ps. With the exception of the terminal residues, the motions of the backbone carbon nuclei of Xfin-31 are highly restricted. Residues 10-13, which form a turn between the beta-sheet and the helix present in the three-dimensional structure of Xfin-31, have a slightly higher mobility than the rest of the interior backbone, and the two residues at the C-terminus have considerable conformational flexibility. The side chains of the hydrophobic Val and Leu residues are more mobile than the backbone but are still significantly restricted, which indicates that Xfin-31 is compact despite its small size. Systematically large spin-spin relaxation rates for residues in the zinc binding site imply that conformational exchange may occur in this region on a time scale longer than the overall rotational correlation time.

Title: BACKBONE DYNAMICS OF ESCHERICHIA-COLI RIBONUCLEASE HI - CORRELATIONS WITH STRUCTURE AND FUNCTION IN AN ACTIVE ENZYME (#30)

Source: JOURNAL OF MOLECULAR BIOLOGY 246 (1): 144-163 FEB 10 1995

Cited References: 102 Times Cited: 379

Abstract: Ribonuclease H is an endonuclease that hydrolyzes the RNA moiety of RNA-DNA duplex molecules. Escherichia coli ribonuclease H is involved in DNA replication, and retroviral ribonuclease H is essential for reverse transcription of the viral genome. To characterize the intramolecular dynamical properties of E. coli ribonuclease H, spin-lattice relaxation rate constants, spin-spin relaxation rate constants and steady state nuclear Overhauser effects for the N-15 nuclear spins were measured by using proton-detected heteronuclear NMR spectroscopy; The relaxation data were analyzed by using a series of dynamical models in conjunction with a statistical model selection protocol. Ribonuclease H exhibits a complex array of dynamical features, most notably in the parallel beta-strands of the principal five-stranded beta-sheet, the coiled-coil helical interface, the active site, and the loop regions surrounding the active site. The dynamical properties are correlated with local structural environments of the N-15 spins and suggest possible relationships to the functional properties of ribonuclease H. Results for E. coli ribonuclease H are compared to previously reported results for the human immunodeficiancy virus type 1 ribonuclease H domain of reverse transcriptase.

Title: SUPPRESSION OF THE EFFECTS OF CROSS-CORRELATION BETWEEN DIPOLAR AND ANISOTROPIC CHEMICAL-SHIFT RELAXATION MECHANISMS IN THE MEASUREMENT OF SPIN SPIN RELAXATION RATES (#90)

Source: MOLECULAR PHYSICS 75 (3): 699-711 FEB 20 1992

Cited References: 53 Times Cited: 220

Abstract: Cross correlation between dipolar and anisotropic chemical shift relaxation mechanisms complicates measurements of heteronuclear spin-spin relaxation rate constants by the Carr-Purcell-Meiboom-Gill (CPMG) technique if the magnitudes of the chemical shift anisotropy and the dipolar interaction are comparable. Experimental schemes are described that attenuate the effects of cross correlation and permit accurate measurements of spin-spin relaxation rate constants for heteronuclei with significant chemical shift anisotropies. The theoretical analysis is confirmed by measurements of N-15 and C-13 spin-spin relaxation in a peptide. Application of 180-degrees pulses to the protons directly attached to the heteronuclei in synchrony with the even echoes of the heteronuclear spins yields more accurate results than continuous irradiation of the protons with a composite pulse decoupling sequence or application of a single 180-degrees pulse to the protons in the middle of the CPMG pulse train.

Title: LONG-RANGE HYDROGEN-BOND MEDIATED EFFECTS IN PEPTIDES - N-15 NMR-STUDY OF GRAMICIDIN-S IN WATER AND ORGANIC-SOLVENTS (#108)

Source: JOURNAL OF THE AMERICAN CHEMICAL SOCIETY 106 (7): 1939-1941 1984

Cited References: 20 Times Cited: 208

Title: Structural and dynamic characterization of partially folded states of apomyoglobin and implications for protein folding (#127)

Source: NATURE STRUCTURAL BIOLOGY 5 (2): 148-155 FEB 1998

Cited References: 57 Times Cited: 191

Abstract: The structure and dynamics of two partially folded states of apomyoglobin have been characterized at equilibrium using multi-dimensional NMR spectroscopy. Residue-specific measurements of chemical shift and internal dynamics in these states and in the native apoprotein and holoprotein indicate progressive accumulation of secondary structure and increasing restriction of backbone dynamics as the chain collapses to form increasingly compact states. Under weakly folding conditions, the polypeptide fluctuates between unfolded states and local elements of structure that become extended and stabilized as the chain becomes more compact. These results provide a detailed model for molecular events that are likely to occur during folding of myoglobin.

The 20 Most-Frequently-Cited Chemistry in PNAS as of 01/02/2005 - 5/2006 -- updated monthly

Most-cited rankings are recalculated at the beginning of the month. Rankings are based on citations to articles on this journal site from articles in HighWire-hosted journals.

http://www.nysbc.net/library//20021103.bak/20021103.bak/new.pdf/10359756.pdf Rank 1. Y. Oda, K. Huang, F. R. Cross, D. Cowburn, B. T. Chait Accurate quantitation of protein expression and site-specific phosphorylation PNAS Jun 08, 1999 96: 6591-6596.

Papers with high citation statistics associated with NYSBC investigators

NMR/ Structural Biology

Cited References: 29 Times Cited: 308

Abstract: Histone acetylation is important in chromatin remodelling and gene activation(1-4). Nearly all known histone-acetyltransferase (HAT)-associated transcriptional co-activators contain bromodomains, which are similar to 110-amino-acid modules found in many chromatin-associated proteins(5-9). Despite the wide occurrence of these bromodomains, their three-dimensional structure and binding partners remain unknown. Here we report the solution structure of the bromodomain of the HAT co-activator P/CAF (p300/CBP-associated factor)(10,11). The structure reveals an unusual left-handed up-and-down four-helix bundle. In addition, we show by a combination of structural and site-directed mutagenesis studies that bromodomains can interact specifically with acetylated lysine, making them the first known protein modules to do so, The nature of the recognition of acetyl-lysine by the P/CAF bromodomain is similar to that of acetyl-CoA by histone acetyltransferase. Thus, the bromodomain is functionally linked to the HAT activity of co-activators in the regulation of gene transcription.

Title: MOLECULAR-BASIS OF HUMAN 46X,Y SEX REVERSAL REVEALED FROM THE 3-DIMENSIONAL SOLUTION STRUCTURE OF THE HUMAN SRY-DNA COMPLEX (#69 of > 20000 Oct 2005)

Source: CELL 81 (5): 705-714 JUN 2 1995

Cited References: 49 Times Cited: 293

Abstract: The solution structure of the specific complex between the high mobility group (HMG) domain of SRY (hSRY-HMG), the protein encoded by the human testis-determining gene, and its DNA target site in the promoter of the Mullerian inhibitory substance gene has been determined by multidimensional NMR spectroscopy. hSRY-HMG has a twisted L shape that presents a concave surface (made up of three helices and the N- and C-terminal strands) to the DNA for sequence-specific recognition. Binding of hSRY-HMG to its specific target site occurs exclusively in the minor groove and induces a large conformational change in the DNA. The DNA in the complex has an overall 70 degrees-80 degrees bend and is helically unwound relative to classical A- and B-DNA. The structure of the complex reveals the origin of sequence-specific binding within the HMG-1/HMG-2 family and provides a framework for understanding the effects of point mutations that cause 46X, Y sex reversal at the atomic level.

Source: ANNUAL REVIEW OF BIOPHYSICS AND BIOMOLECULAR STRUCTURE 26: 259-288 1997

Cited References: 104 Times Cited: 239

Abstract: A characteristic feature of cellular signal transduction pathways in eukaryotes is the separation of catalysis from target recognition. Several modular domains that recognize short peptide sequences and target signaling proteins to these sequences have been identified. The structural bases of the specificities of recognition by SH2, SH3, and PTB domains have been elucidated by X-ray crystallography and NMR, and these results are reviewed here. In addition, the mechanism of cooperative interactions between these domains is discussed.

Title: Structural changes linked to proton translocation by subunit c of the ATP synthase (#195 of > 20000 Oct 05)

Source: NATURE 402 (6759): 263-268 NOV 18 1999

Cited References: 50 Times Cited: 179

Abstract: F1F0 ATP synthases use a transmembrane proton gradient to drive the synthesis of cellular ATP. The structure of the cytosolic F-1 portion of the enzyme and the basic mechanism of ATP hydrolysis by F-1 are now well established, but how proton translocation through the transmembrane F-0 portion drives these catalytic changes is less clear. Here we describe the structural changes in the proton-translocating F-0 subunit c that are induced by deprotonating the specific aspartic acid involved in proton transport. conformational changes between the protonated and deprotonated forms of subunit c provide the structural basis for an explicit mechanism to explain coupling of proton translocation by F-0 to the rotation of subunits within the core of F-1. Rotation of these subunits within F-1 causes the catalytic conformational changes in the active sites of F-1 that result in ATP synthesis.

Title: SOLUTION STRUCTURE OF THE HUMAN TELOMERIC REPEAT D[AG(3)(T(2)AG(3))3] G-TETRAPLEX (#196 of > 20000 Oct 05)

Source: STRUCTURE 1 (4): 263-282 DEC 15 1993

Cited References: 55 Times Cited: 179

Abstract: Background: Repeats of G, sequences are detected as single strand overhangs at the ends of eukaryotic chromosomes together with associated binding proteins. Such telomere sequences have been implicated in the replication and maintenance of chromosomal termini. They may also mediate chromosomal organization and association during meiosis and mitosis.

Results: We have determined the three-dimensional solution structure of the human telomere sequence, d[AG(3)(T(2)AG(3))(3)] in Na+-containing solution using a combined NMR, distance geometry and molecular dynamics approach (including relaxation matrix refinement). The sequence, which contains four AG(3) repeats, folds intramolecularly into a G-tetraplex stabilized by three stacked G-tetrads which are connected by two lateral loops and a central diagonal loop. Of the four grooves chat are formed, one is wide, two are of medium width and one is narrow. The alignment of adjacent G-G-G segments in parallel generates the two grooves of medium width whilst the antiparallel arrangement results in one wide and one narrow groove. Three of the four adenines stack on top of adjacent G-tetrads while the majority of the thymines sample multiple conformations.

Conclusions: The availability of the d[AG(3)(T(2)AG(3))(3)] solution structure containing four AG(3) human telomeric repeats should permit the rational design of ligands that recognize and bind with specificity and affinity to the individual grooves of the G-tetraplex, as well as to either end containing the diagonal and lateral loops. Such ligands could modulate the equilibrium between folded G-tetraplex structures and their unfolded extended counterparts.

Source: CELL 96 (5): 625-634 MAR 5 1999

Cited References: 66 Times Cited: 169

Abstract: Members of the BCL2 family of proteins are key regulators of programmed cell death, acting either as apoptotic agonists or antagonists. Here we describe the solution structure of BID, presenting the structure of a proapoptotic BCL2 family member. An analysis of sequence/structure of BCL2 family members allows us to define a structural superfamily, which has implications for general mechanisms for regulating proapoptotic activity. It appears two criteria must be met for proapoptotic function within the BCL2 family: targeting of molecules to intracellular membranes, and exposure of the BH3 death domain. BID's activity is regulated by a Caspase 8-mediated cleavage event, exposing the BH3 domain and significantly changing the surface charge and hydrophobicity, resulting in a change of cellular localization.

Title: Nuclear magnetic resonance studies of biopolymer dynamics (#235 of > 20000 Oct 05)

Source: JOURNAL OF PHYSICAL CHEMISTRY 100 (31): 13293-13310 AUG 1 1996

Cited References: 190 Times Cited: 166

Abstract: NMR spectroscopy is a powerful approach for quantitating molecular conformational dynamics at multiple atomic sites and over multiple time scales. Extensive studies by solution and solid-state NMR spectroscopy of spin relaxation and line shapes in biological macromolecules have been performed in order to characterize the amplitudes, time scales, and energetics of intramolecular conformational modes and to elucidate the relationships between conformational dynamics, structure, and function. This review describes NMR spectroscopic methods for investigation of conformational dynamics together with theoretical descriptions appropriate for interpretation and simulation of the techniques, surveys the range of results available from solution and solid state NMR studies of proteins and other biomolecules, and identifies opportunities for further individual and collaborative development of solution and solid state NMR techniques for characterizing the dynamical properties of biological macromolecules.

Title: BACKBONE DYNAMICS OF CALCIUM-LOADED CALBINDIN-D(9K) STUDIED BY 2-DIMENSIONAL PROTON-DETECTED N-15 NMR-SPECTROSCOPY (#292 of > 20000 Oct 05)

Source: BIOCHEMISTRY 31 (20): 4856-4866 MAY 26 1992

Cited References: 67 Times Cited: 162

Abstract: Backbone dynamics of calcium-loaded calbindin D9k have been investigated by two-dimensional proton-detected heteronuclear nuclear magnetic resonance spectroscopy, using a uniformly N-15 enriched protein sample. Spin-lattice relaxation rate constants, spin-spin relaxation rate constants, and steady-state {H-1}-N-15 nuclear Overhauser effects were determined for 71 of the 72 backbone amide N-15 nuclei. The relaxation parameters were analyzed using a model-free formalism that incorporates the overall rotational correlation time of the molecule, and a generalized order parameter (S2) and an effective internal correlation time for each amide group. Calbindin D9k contains two helix-loop-helix motifs joined by a linker loop at one end of the protein and a beta-type interaction between the two calcium-binding loops at the other end. The amplitude of motions for the calcium-binding loops and the helices are similar, as judged from the average S2 values of 0.83 +/- 0.05 and 0.85 +/- 0.04, respectively. The linker region joining the two calcium-binding subdomains of the molecule has a significantly higher flexibility, as indicated by a substantially lower average S2 value of 0.59 +/- 0.23. For residues in the linker loop and at the C-terminus, the order parameter is further decomposed into separate order parameters for motional processes on two distinct time scales. The effective correlation times are significantly longer for helices I and IV than for helices II and III or for the calcium-binding loops. Residue by residue comparisons reveal correlations of the order parameters with both the crystallographic B-factors and amide proton exchange rates, despite vast differences in the time scales to which these properties are sensitive. The order parameters are also utilized to distinguish regions of the NMR-derived three-dimensional structure of calbindin D9k that are poorly defined due to inherently high flexibility, from poorly defined regions with average flexibility but a low density of structural constraints.

Title: PROTEIN DYNAMICS STUDIED BY ROTATING FRAME N-15 SPIN RELAXATION-TIMES (#276 of 20000, Oct 05)

Source: JOURNAL OF BIOMOLECULAR NMR 3 (2): 151-164 MAR 1993

Cited References: 48 Times Cited: 153

Abstract: Conformational rate processes in aqueous solutions of uniformly N-15-labeled pancreatic trypsin inhibitor (BPTI) at 36-degrees-C were investigated by measuring the rotating frame relaxation times of the backbone N-15 spins as a function of the spin-lock power, Two different intramolecular exchange processes were identified. A first local rate process involved the residues Cys38 and Arg39, had a correlation time of about 1.3 ms, and was related to isomerization of the chirality of the disulfide bond Cys14-Cys38. A second, faster motional mode was superimposed on the disulfide bond isomerization and was tentatively attributed to local segmental motions in the polypeptide sequence - Cys14 - Ala15 - Lys16 -. The correlation time for the overall rotational tumbling of the protein was found to be 2 ns, using the assumption that relaxation is dominated by dipolar coupling and chemical shift anistropy modulated by isotropic molecular reorientation.

Title: Solution structure of the transmembrane H+-transporting subunit c of the F1F0 ATP synthase (#283 of >20000 Oct 05)

Source: BIOCHEMISTRY 37 (25): 8817-8824 JUN 23 1998

Cited References: 56 Times Cited: 151

Abstract: Subunit c is the H+-translocating component of the F1F0 ATP synthase complex. H+ transport is coupled to conformational changes that ultimately lead to ATP synthesis by the enzyme. The properties of the monomeric subunit in a single phase solution of chloroform-methanol - water (4:4:1) have been shown to mimic those of the protein in the native complex. Triple resonance NMR experiments were used to determine the complete structure of monomeric subunit c in this solvent mixture. The structure of the protein was defined by >2000 interproton distances, 64 (3)J(N alpha), and 43 hydrogen-bonding NMR-derived restraints. The root mean squared deviation for the backbone atoms of the two transmembrane helices was 0.63 Angstrom. The protein folds as a hairpin of two antiparallel helical segments, connected by a short structured loop. The conserved Arg41-Gln42-Pro43 form the top of this loop. The essential H+-transporting Asp61 residue is located at a slight break in the middle of the C-terminal helix, just prior to Pro64. The C-terminal helix changes direction by 30 +/- 5 degrees at the conserved Pro64. In its protonated form, the Asp61 lies in a cavity created by the absence of side chains at Gly23 and Gly27 in the N-terminal helix. The shape and charge distribution of the molecular surface of the monomeric protein suggest a packing arrangement for the oligomeric protein in the F-o complex, with the front face of one monomer packing favorably against the back face of a second monomer. The packing suggests that the proton (cation) binding site lies between packed pairs of adjacent subunit c.

NMR / Related techniques

Title: INTRAMOLECULAR MOTIONS OF A ZINC FINGER DNA-BINDING DOMAIN FROM XFIN CHARACTERIZED BY PROTON-DETECTED NATURAL ABUNDANCE C-12 HETERONUCLEAR NMR-SPECTROSCOPY (#28)

Source: JOURNAL OF THE AMERICAN CHEMICAL SOCIETY 113 (12): 4371-4380 JUN 5 1991

Cited References: 91 Times Cited: 384

Abstract: The zinc finger DNA-binding domain Xfin-31 is a 25-residue peptide that binds a single zinc atom and forms a compact globular structure in solution. To characterize the intramolecular dynamics of Xfin-31, the C-13 spin-lattice and spin-spin relaxation rate constants and the {H-1}-C-13 nuclear Overhauser effect (NOE) enhancements have been measured for the backbone and side chain methine carbons by two-dimensional proton-detected heteronuclear NMR spectroscopy at a C-13 Larmor frequency of 125 MHz and natural C-13 abundance. The relaxation rate constants and the NOE enhancements have been analyzed by using a model-free formalism that depends on the overall rotational correlation time of the molecule, tau-m, the order parameter S, and effective internal correlation time, tau-e, for each methine carbon. The optimized global value of tau-m is 1.88 +/- 0.02 ns. The backbone C-alpha carbons are grouped into four categories based on the values of the order parameters: the N-terminal residue Tyr1 with S2 = 0.73 +/- 0.04; the C-terminal residues Lys24 and Asn25 with S2 < 0.5; residues Phe10-Lysl3 with an average S2 = 0.77 +/- 0.03; and the remainder of the backbone carbon nuclei with an average S2 = 0.89 +/- 0.05. For the side chain C-beta of Val11 and Val22 and the C-gamma of Leu5, the values of S2 are 0.62 +/- 0.03, 0.66 +/- 0.04, and 0.47 +/- 0.03, respectively. Estimates of tau-e could be obtained for 13 of the backbone and 3 of the side chain methine carbons. Excluding the terminal residues, the average value of tau-e for the backbone carbon nuclei was 34 +/- 16 ps. With the exception of the terminal residues, the motions of the backbone carbon nuclei of Xfin-31 are highly restricted. Residues 10-13, which form a turn between the beta-sheet and the helix present in the three-dimensional structure of Xfin-31, have a slightly higher mobility than the rest of the interior backbone, and the two residues at the C-terminus have considerable conformational flexibility. The side chains of the hydrophobic Val and Leu residues are more mobile than the backbone but are still significantly restricted, which indicates that Xfin-31 is compact despite its small size. Systematically large spin-spin relaxation rates for residues in the zinc binding site imply that conformational exchange may occur in this region on a time scale longer than the overall rotational correlation time.

Title: BACKBONE DYNAMICS OF ESCHERICHIA-COLI RIBONUCLEASE HI - CORRELATIONS WITH STRUCTURE AND FUNCTION IN AN ACTIVE ENZYME (#30)

Source: JOURNAL OF MOLECULAR BIOLOGY 246 (1): 144-163 FEB 10 1995

Cited References: 102 Times Cited: 379

Abstract: Ribonuclease H is an endonuclease that hydrolyzes the RNA moiety of RNA-DNA duplex molecules. Escherichia coli ribonuclease H is involved in DNA replication, and retroviral ribonuclease H is essential for reverse transcription of the viral genome. To characterize the intramolecular dynamical properties of E. coli ribonuclease H, spin-lattice relaxation rate constants, spin-spin relaxation rate constants and steady state nuclear Overhauser effects for the N-15 nuclear spins were measured by using proton-detected heteronuclear NMR spectroscopy; The relaxation data were analyzed by using a series of dynamical models in conjunction with a statistical model selection protocol. Ribonuclease H exhibits a complex array of dynamical features, most notably in the parallel beta-strands of the principal five-stranded beta-sheet, the coiled-coil helical interface, the active site, and the loop regions surrounding the active site. The dynamical properties are correlated with local structural environments of the N-15 spins and suggest possible relationships to the functional properties of ribonuclease H. Results for E. coli ribonuclease H are compared to previously reported results for the human immunodeficiancy virus type 1 ribonuclease H domain of reverse transcriptase.

Title: SUPPRESSION OF THE EFFECTS OF CROSS-CORRELATION BETWEEN DIPOLAR AND ANISOTROPIC CHEMICAL-SHIFT RELAXATION MECHANISMS IN THE MEASUREMENT OF SPIN SPIN RELAXATION RATES (#90)

Source: MOLECULAR PHYSICS 75 (3): 699-711 FEB 20 1992

Cited References: 53 Times Cited: 220

Abstract: Cross correlation between dipolar and anisotropic chemical shift relaxation mechanisms complicates measurements of heteronuclear spin-spin relaxation rate constants by the Carr-Purcell-Meiboom-Gill (CPMG) technique if the magnitudes of the chemical shift anisotropy and the dipolar interaction are comparable. Experimental schemes are described that attenuate the effects of cross correlation and permit accurate measurements of spin-spin relaxation rate constants for heteronuclei with significant chemical shift anisotropies. The theoretical analysis is confirmed by measurements of N-15 and C-13 spin-spin relaxation in a peptide. Application of 180-degrees pulses to the protons directly attached to the heteronuclei in synchrony with the even echoes of the heteronuclear spins yields more accurate results than continuous irradiation of the protons with a composite pulse decoupling sequence or application of a single 180-degrees pulse to the protons in the middle of the CPMG pulse train.

Title: LONG-RANGE HYDROGEN-BOND MEDIATED EFFECTS IN PEPTIDES - N-15 NMR-STUDY OF GRAMICIDIN-S IN WATER AND ORGANIC-SOLVENTS (#108)

Source: JOURNAL OF THE AMERICAN CHEMICAL SOCIETY 106 (7): 1939-1941 1984

Cited References: 20 Times Cited: 208

Title: Structural and dynamic characterization of partially folded states of apomyoglobin and implications for protein folding (#127)

Source: NATURE STRUCTURAL BIOLOGY 5 (2): 148-155 FEB 1998

Cited References: 57 Times Cited: 191

Abstract: The structure and dynamics of two partially folded states of apomyoglobin have been characterized at equilibrium using multi-dimensional NMR spectroscopy. Residue-specific measurements of chemical shift and internal dynamics in these states and in the native apoprotein and holoprotein indicate progressive accumulation of secondary structure and increasing restriction of backbone dynamics as the chain collapses to form increasingly compact states. Under weakly folding conditions, the polypeptide fluctuates between unfolded states and local elements of structure that become extended and stabilized as the chain becomes more compact. These results provide a detailed model for molecular events that are likely to occur during folding of myoglobin.

The 20 Most-Frequently-Cited Chemistry in PNAS as of 01/02/2005 - 5/2006 -- updated monthly

Most-cited rankings are recalculated at the beginning of the month. Rankings are based on citations to articles on this journal site from articles in HighWire-hosted journals.

http://www.nysbc.net/library//20021103.bak/20021103.bak/new.pdf/10359756.pdf Rank 1. Y. Oda, K. Huang, F. R. Cross, D. Cowburn, B. T. Chait Accurate quantitation of protein expression and site-specific phosphorylation PNAS Jun 08, 1999 96: 6591-6596.

Papers with high citation statistics associated with NYSBC investigators

NMR/ Structural Biology

Title: Structure and ligand of a histone acetyltransferase bromodomain ( #64 of >20,000 related Oct 2005)

Cited References: 29 Times Cited: 308

Abstract: Histone acetylation is important in chromatin remodelling and gene activation(1-4). Nearly all known histone-acetyltransferase (HAT)-associated transcriptional co-activators contain bromodomains, which are similar to 110-amino-acid modules found in many chromatin-associated proteins(5-9). Despite the wide occurrence of these bromodomains, their three-dimensional structure and binding partners remain unknown. Here we report the solution structure of the bromodomain of the HAT co-activator P/CAF (p300/CBP-associated factor)(10,11). The structure reveals an unusual left-handed up-and-down four-helix bundle. In addition, we show by a combination of structural and site-directed mutagenesis studies that bromodomains can interact specifically with acetylated lysine, making them the first known protein modules to do so, The nature of the recognition of acetyl-lysine by the P/CAF bromodomain is similar to that of acetyl-CoA by histone acetyltransferase. Thus, the bromodomain is functionally linked to the HAT activity of co-activators in the regulation of gene transcription.

Title: MOLECULAR-BASIS OF HUMAN 46X,Y SEX REVERSAL REVEALED FROM THE 3-DIMENSIONAL SOLUTION STRUCTURE OF THE HUMAN SRY-DNA COMPLEX (#69 of > 20000 Oct 2005)

Cited References: 49 Times Cited: 293

Abstract: The solution structure of the specific complex between the high mobility group (HMG) domain of SRY (hSRY-HMG), the protein encoded by the human testis-determining gene, and its DNA target site in the promoter of the Mullerian inhibitory substance gene has been determined by multidimensional NMR spectroscopy. hSRY-HMG has a twisted L shape that presents a concave surface (made up of three helices and the N- and C-terminal strands) to the DNA for sequence-specific recognition. Binding of hSRY-HMG to its specific target site occurs exclusively in the minor groove and induces a large conformational change in the DNA. The DNA in the complex has an overall 70 degrees-80 degrees bend and is helically unwound relative to classical A- and B-DNA. The structure of the complex reveals the origin of sequence-specific binding within the HMG-1/HMG-2 family and provides a framework for understanding the effects of point mutations that cause 46X, Y sex reversal at the atomic level.

Title: Modular peptide recognition domains in eukaryotic signaling (review, #98 of > 20000 Oct 2005)

Source: ANNUAL REVIEW OF BIOPHYSICS AND BIOMOLECULAR STRUCTURE 26: 259-288 1997

Cited References: 104 Times Cited: 239

Abstract: A characteristic feature of cellular signal transduction pathways in eukaryotes is the separation of catalysis from target recognition. Several modular domains that recognize short peptide sequences and target signaling proteins to these sequences have been identified. The structural bases of the specificities of recognition by SH2, SH3, and PTB domains have been elucidated by X-ray crystallography and NMR, and these results are reviewed here. In addition, the mechanism of cooperative interactions between these domains is discussed.

Title: Structural changes linked to proton translocation by subunit c of the ATP synthase (#195 of > 20000 Oct 05)

Source: NATURE 402 (6759): 263-268 NOV 18 1999

Cited References: 50 Times Cited: 179

Abstract: F1F0 ATP synthases use a transmembrane proton gradient to drive the synthesis of cellular ATP. The structure of the cytosolic F-1 portion of the enzyme and the basic mechanism of ATP hydrolysis by F-1 are now well established, but how proton translocation through the transmembrane F-0 portion drives these catalytic changes is less clear. Here we describe the structural changes in the proton-translocating F-0 subunit c that are induced by deprotonating the specific aspartic acid involved in proton transport. conformational changes between the protonated and deprotonated forms of subunit c provide the structural basis for an explicit mechanism to explain coupling of proton translocation by F-0 to the rotation of subunits within the core of F-1. Rotation of these subunits within F-1 causes the catalytic conformational changes in the active sites of F-1 that result in ATP synthesis.

Title: SOLUTION STRUCTURE OF THE HUMAN TELOMERIC REPEAT D[AG(3)(T(2)AG(3))3] G-TETRAPLEX (#196 of > 20000 Oct 05)

Source: STRUCTURE 1 (4): 263-282 DEC 15 1993

Cited References: 55 Times Cited: 179

Abstract: Background: Repeats of G, sequences are detected as single strand overhangs at the ends of eukaryotic chromosomes together with associated binding proteins. Such telomere sequences have been implicated in the replication and maintenance of chromosomal termini. They may also mediate chromosomal organization and association during meiosis and mitosis.

Results: We have determined the three-dimensional solution structure of the human telomere sequence, d[AG(3)(T(2)AG(3))(3)] in Na+-containing solution using a combined NMR, distance geometry and molecular dynamics approach (including relaxation matrix refinement). The sequence, which contains four AG(3) repeats, folds intramolecularly into a G-tetraplex stabilized by three stacked G-tetrads which are connected by two lateral loops and a central diagonal loop. Of the four grooves chat are formed, one is wide, two are of medium width and one is narrow. The alignment of adjacent G-G-G segments in parallel generates the two grooves of medium width whilst the antiparallel arrangement results in one wide and one narrow groove. Three of the four adenines stack on top of adjacent G-tetrads while the majority of the thymines sample multiple conformations.

Conclusions: The availability of the d[AG(3)(T(2)AG(3))(3)] solution structure containing four AG(3) human telomeric repeats should permit the rational design of ligands that recognize and bind with specificity and affinity to the individual grooves of the G-tetraplex, as well as to either end containing the diagonal and lateral loops. Such ligands could modulate the equilibrium between folded G-tetraplex structures and their unfolded extended counterparts.

Title: Solution structure of the proapoptotic molecule BID: A structural basis for apoptotic agonists and antagonists (#226 of > 20000 Oct 05)

Author(s): McDonnell JM, Fushman D, Milliman CL, Korsmeyer SJ, Cowburn D

Source: CELL 96 (5): 625-634 MAR 5 1999

Cited References: 66 Times Cited: 169

Abstract: Members of the BCL2 family of proteins are key regulators of programmed cell death, acting either as apoptotic agonists or antagonists. Here we describe the solution structure of BID, presenting the structure of a proapoptotic BCL2 family member. An analysis of sequence/structure of BCL2 family members allows us to define a structural superfamily, which has implications for general mechanisms for regulating proapoptotic activity. It appears two criteria must be met for proapoptotic function within the BCL2 family: targeting of molecules to intracellular membranes, and exposure of the BH3 death domain. BID's activity is regulated by a Caspase 8-mediated cleavage event, exposing the BH3 domain and significantly changing the surface charge and hydrophobicity, resulting in a change of cellular localization.

Title: Nuclear magnetic resonance studies of biopolymer dynamics (#235 of > 20000 Oct 05)

Source: JOURNAL OF PHYSICAL CHEMISTRY 100 (31): 13293-13310 AUG 1 1996

Cited References: 190 Times Cited: 166

Abstract: NMR spectroscopy is a powerful approach for quantitating molecular conformational dynamics at multiple atomic sites and over multiple time scales. Extensive studies by solution and solid-state NMR spectroscopy of spin relaxation and line shapes in biological macromolecules have been performed in order to characterize the amplitudes, time scales, and energetics of intramolecular conformational modes and to elucidate the relationships between conformational dynamics, structure, and function. This review describes NMR spectroscopic methods for investigation of conformational dynamics together with theoretical descriptions appropriate for interpretation and simulation of the techniques, surveys the range of results available from solution and solid state NMR studies of proteins and other biomolecules, and identifies opportunities for further individual and collaborative development of solution and solid state NMR techniques for characterizing the dynamical properties of biological macromolecules.

Title: BACKBONE DYNAMICS OF CALCIUM-LOADED CALBINDIN-D(9K) STUDIED BY 2-DIMENSIONAL PROTON-DETECTED N-15 NMR-SPECTROSCOPY (#292 of > 20000 Oct 05)

Source: BIOCHEMISTRY 31 (20): 4856-4866 MAY 26 1992

Cited References: 67 Times Cited: 162

Abstract: Backbone dynamics of calcium-loaded calbindin D9k have been investigated by two-dimensional proton-detected heteronuclear nuclear magnetic resonance spectroscopy, using a uniformly N-15 enriched protein sample. Spin-lattice relaxation rate constants, spin-spin relaxation rate constants, and steady-state {H-1}-N-15 nuclear Overhauser effects were determined for 71 of the 72 backbone amide N-15 nuclei. The relaxation parameters were analyzed using a model-free formalism that incorporates the overall rotational correlation time of the molecule, and a generalized order parameter (S2) and an effective internal correlation time for each amide group. Calbindin D9k contains two helix-loop-helix motifs joined by a linker loop at one end of the protein and a beta-type interaction between the two calcium-binding loops at the other end. The amplitude of motions for the calcium-binding loops and the helices are similar, as judged from the average S2 values of 0.83 +/- 0.05 and 0.85 +/- 0.04, respectively. The linker region joining the two calcium-binding subdomains of the molecule has a significantly higher flexibility, as indicated by a substantially lower average S2 value of 0.59 +/- 0.23. For residues in the linker loop and at the C-terminus, the order parameter is further decomposed into separate order parameters for motional processes on two distinct time scales. The effective correlation times are significantly longer for helices I and IV than for helices II and III or for the calcium-binding loops. Residue by residue comparisons reveal correlations of the order parameters with both the crystallographic B-factors and amide proton exchange rates, despite vast differences in the time scales to which these properties are sensitive. The order parameters are also utilized to distinguish regions of the NMR-derived three-dimensional structure of calbindin D9k that are poorly defined due to inherently high flexibility, from poorly defined regions with average flexibility but a low density of structural constraints.

Title: PROTEIN DYNAMICS STUDIED BY ROTATING FRAME N-15 SPIN RELAXATION-TIMES (#276 of 20000, Oct 05)

Source: JOURNAL OF BIOMOLECULAR NMR 3 (2): 151-164 MAR 1993

Cited References: 48 Times Cited: 153

Abstract: Conformational rate processes in aqueous solutions of uniformly N-15-labeled pancreatic trypsin inhibitor (BPTI) at 36-degrees-C were investigated by measuring the rotating frame relaxation times of the backbone N-15 spins as a function of the spin-lock power, Two different intramolecular exchange processes were identified. A first local rate process involved the residues Cys38 and Arg39, had a correlation time of about 1.3 ms, and was related to isomerization of the chirality of the disulfide bond Cys14-Cys38. A second, faster motional mode was superimposed on the disulfide bond isomerization and was tentatively attributed to local segmental motions in the polypeptide sequence - Cys14 - Ala15 - Lys16 -. The correlation time for the overall rotational tumbling of the protein was found to be 2 ns, using the assumption that relaxation is dominated by dipolar coupling and chemical shift anistropy modulated by isotropic molecular reorientation.

Title: Solution structure of the transmembrane H+-transporting subunit c of the F1F0 ATP synthase (#283 of >20000 Oct 05)

Source: BIOCHEMISTRY 37 (25): 8817-8824 JUN 23 1998

Cited References: 56 Times Cited: 151

Abstract: Subunit c is the H+-translocating component of the F1F0 ATP synthase complex. H+ transport is coupled to conformational changes that ultimately lead to ATP synthesis by the enzyme. The properties of the monomeric subunit in a single phase solution of chloroform-methanol - water (4:4:1) have been shown to mimic those of the protein in the native complex. Triple resonance NMR experiments were used to determine the complete structure of monomeric subunit c in this solvent mixture. The structure of the protein was defined by >2000 interproton distances, 64 (3)J(N alpha), and 43 hydrogen-bonding NMR-derived restraints. The root mean squared deviation for the backbone atoms of the two transmembrane helices was 0.63 Angstrom. The protein folds as a hairpin of two antiparallel helical segments, connected by a short structured loop. The conserved Arg41-Gln42-Pro43 form the top of this loop. The essential H+-transporting Asp61 residue is located at a slight break in the middle of the C-terminal helix, just prior to Pro64. The C-terminal helix changes direction by 30 +/- 5 degrees at the conserved Pro64. In its protonated form, the Asp61 lies in a cavity created by the absence of side chains at Gly23 and Gly27 in the N-terminal helix. The shape and charge distribution of the molecular surface of the monomeric protein suggest a packing arrangement for the oligomeric protein in the F-o complex, with the front face of one monomer packing favorably against the back face of a second monomer. The packing suggests that the proton (cation) binding site lies between packed pairs of adjacent subunit c.

NMR / Related techniques

Title: INTRAMOLECULAR MOTIONS OF A ZINC FINGER DNA-BINDING DOMAIN FROM XFIN CHARACTERIZED BY PROTON-DETECTED NATURAL ABUNDANCE C-12 HETERONUCLEAR NMR-SPECTROSCOPY (#28)

Source: JOURNAL OF THE AMERICAN CHEMICAL SOCIETY 113 (12): 4371-4380 JUN 5 1991

Cited References: 91 Times Cited: 384

Abstract: The zinc finger DNA-binding domain Xfin-31 is a 25-residue peptide that binds a single zinc atom and forms a compact globular structure in solution. To characterize the intramolecular dynamics of Xfin-31, the C-13 spin-lattice and spin-spin relaxation rate constants and the {H-1}-C-13 nuclear Overhauser effect (NOE) enhancements have been measured for the backbone and side chain methine carbons by two-dimensional proton-detected heteronuclear NMR spectroscopy at a C-13 Larmor frequency of 125 MHz and natural C-13 abundance. The relaxation rate constants and the NOE enhancements have been analyzed by using a model-free formalism that depends on the overall rotational correlation time of the molecule, tau-m, the order parameter S, and effective internal correlation time, tau-e, for each methine carbon. The optimized global value of tau-m is 1.88 +/- 0.02 ns. The backbone C-alpha carbons are grouped into four categories based on the values of the order parameters: the N-terminal residue Tyr1 with S2 = 0.73 +/- 0.04; the C-terminal residues Lys24 and Asn25 with S2 < 0.5; residues Phe10-Lysl3 with an average S2 = 0.77 +/- 0.03; and the remainder of the backbone carbon nuclei with an average S2 = 0.89 +/- 0.05. For the side chain C-beta of Val11 and Val22 and the C-gamma of Leu5, the values of S2 are 0.62 +/- 0.03, 0.66 +/- 0.04, and 0.47 +/- 0.03, respectively. Estimates of tau-e could be obtained for 13 of the backbone and 3 of the side chain methine carbons. Excluding the terminal residues, the average value of tau-e for the backbone carbon nuclei was 34 +/- 16 ps. With the exception of the terminal residues, the motions of the backbone carbon nuclei of Xfin-31 are highly restricted. Residues 10-13, which form a turn between the beta-sheet and the helix present in the three-dimensional structure of Xfin-31, have a slightly higher mobility than the rest of the interior backbone, and the two residues at the C-terminus have considerable conformational flexibility. The side chains of the hydrophobic Val and Leu residues are more mobile than the backbone but are still significantly restricted, which indicates that Xfin-31 is compact despite its small size. Systematically large spin-spin relaxation rates for residues in the zinc binding site imply that conformational exchange may occur in this region on a time scale longer than the overall rotational correlation time.

Title: BACKBONE DYNAMICS OF ESCHERICHIA-COLI RIBONUCLEASE HI - CORRELATIONS WITH STRUCTURE AND FUNCTION IN AN ACTIVE ENZYME (#30)

Source: JOURNAL OF MOLECULAR BIOLOGY 246 (1): 144-163 FEB 10 1995

Cited References: 102 Times Cited: 379

Abstract: Ribonuclease H is an endonuclease that hydrolyzes the RNA moiety of RNA-DNA duplex molecules. Escherichia coli ribonuclease H is involved in DNA replication, and retroviral ribonuclease H is essential for reverse transcription of the viral genome. To characterize the intramolecular dynamical properties of E. coli ribonuclease H, spin-lattice relaxation rate constants, spin-spin relaxation rate constants and steady state nuclear Overhauser effects for the N-15 nuclear spins were measured by using proton-detected heteronuclear NMR spectroscopy; The relaxation data were analyzed by using a series of dynamical models in conjunction with a statistical model selection protocol. Ribonuclease H exhibits a complex array of dynamical features, most notably in the parallel beta-strands of the principal five-stranded beta-sheet, the coiled-coil helical interface, the active site, and the loop regions surrounding the active site. The dynamical properties are correlated with local structural environments of the N-15 spins and suggest possible relationships to the functional properties of ribonuclease H. Results for E. coli ribonuclease H are compared to previously reported results for the human immunodeficiancy virus type 1 ribonuclease H domain of reverse transcriptase.

Title: SUPPRESSION OF THE EFFECTS OF CROSS-CORRELATION BETWEEN DIPOLAR AND ANISOTROPIC CHEMICAL-SHIFT RELAXATION MECHANISMS IN THE MEASUREMENT OF SPIN SPIN RELAXATION RATES (#90)

Source: MOLECULAR PHYSICS 75 (3): 699-711 FEB 20 1992

Cited References: 53 Times Cited: 220

Abstract: Cross correlation between dipolar and anisotropic chemical shift relaxation mechanisms complicates measurements of heteronuclear spin-spin relaxation rate constants by the Carr-Purcell-Meiboom-Gill (CPMG) technique if the magnitudes of the chemical shift anisotropy and the dipolar interaction are comparable. Experimental schemes are described that attenuate the effects of cross correlation and permit accurate measurements of spin-spin relaxation rate constants for heteronuclei with significant chemical shift anisotropies. The theoretical analysis is confirmed by measurements of N-15 and C-13 spin-spin relaxation in a peptide. Application of 180-degrees pulses to the protons directly attached to the heteronuclei in synchrony with the even echoes of the heteronuclear spins yields more accurate results than continuous irradiation of the protons with a composite pulse decoupling sequence or application of a single 180-degrees pulse to the protons in the middle of the CPMG pulse train.

Title: LONG-RANGE HYDROGEN-BOND MEDIATED EFFECTS IN PEPTIDES - N-15 NMR-STUDY OF GRAMICIDIN-S IN WATER AND ORGANIC-SOLVENTS (#108)

Source: JOURNAL OF THE AMERICAN CHEMICAL SOCIETY 106 (7): 1939-1941 1984

Cited References: 20 Times Cited: 208

Title: Structural and dynamic characterization of partially folded states of apomyoglobin and implications for protein folding (#127)

Source: NATURE STRUCTURAL BIOLOGY 5 (2): 148-155 FEB 1998

Cited References: 57 Times Cited: 191

Abstract: The structure and dynamics of two partially folded states of apomyoglobin have been characterized at equilibrium using multi-dimensional NMR spectroscopy. Residue-specific measurements of chemical shift and internal dynamics in these states and in the native apoprotein and holoprotein indicate progressive accumulation of secondary structure and increasing restriction of backbone dynamics as the chain collapses to form increasingly compact states. Under weakly folding conditions, the polypeptide fluctuates between unfolded states and local elements of structure that become extended and stabilized as the chain becomes more compact. These results provide a detailed model for molecular events that are likely to occur during folding of myoglobin.

The 20 Most-Frequently-Cited Chemistry in PNAS as of 01/02/2005 - 10/02/2005 -- updated monthly

Most-cited rankings are recalculated at the beginning of the month. Rankings are based on citations to articles on this journal site from articles in HighWire-hosted journals.

http://www.nysbc.net/library//20021103.bak/20021103.bak/new.pdf/10359756.pdf Rank 1. Y. Oda, K. Huang, F. R. Cross, D. Cowburn, B. T. Chait Accurate quantitation of protein expression and site-specific phosphorylation PNAS Jun 08, 1999 96: 6591-6596.

Papers with high citation statistics associated with NYSBC investigators

NMR/ Structural Biology

Title: Structure and ligand of a histone acetyltransferase bromodomain ( #64 of >20,000 related Oct 2005)

Author(s): Dhalluin C, Carlson JE, Zeng L, He C, Aggarwal AK, Zhou MM

Source: NATURE 399 (6735): 491-496 JUN 3 1999

Cited References: 29 Times Cited: 308

Abstract: Histone acetylation is important in chromatin remodelling and gene activation(1-4). Nearly all known histone-acetyltransferase (HAT)-associated transcriptional co-activators contain bromodomains, which are similar to 110-amino-acid modules found in many chromatin-associated proteins(5-9). Despite the wide occurrence of these bromodomains, their three-dimensional structure and binding partners remain unknown. Here we report the solution structure of the bromodomain of the HAT co-activator P/CAF (p300/CBP-associated factor)(10,11). The structure reveals an unusual left-handed up-and-down four-helix bundle. In addition, we show by a combination of structural and site-directed mutagenesis studies that bromodomains can interact specifically with acetylated lysine, making them the first known protein modules to do so, The nature of the recognition of acetyl-lysine by the P/CAF bromodomain is similar to that of acetyl-CoA by histone acetyltransferase. Thus, the bromodomain is functionally linked to the HAT activity of co-activators in the regulation of gene transcription.

Title: MOLECULAR-BASIS OF HUMAN 46X,Y SEX REVERSAL REVEALED FROM THE 3-DIMENSIONAL SOLUTION STRUCTURE OF THE HUMAN SRY-DNA COMPLEX (#69 of > 20000 Oct 2005)

Source: CELL 81 (5): 705-714 JUN 2 1995

Cited References: 49 Times Cited: 293

Abstract: The solution structure of the specific complex between the high mobility group (HMG) domain of SRY (hSRY-HMG), the protein encoded by the human testis-determining gene, and its DNA target site in the promoter of the Mullerian inhibitory substance gene has been determined by multidimensional NMR spectroscopy. hSRY-HMG has a twisted L shape that presents a concave surface (made up of three helices and the N- and C-terminal strands) to the DNA for sequence-specific recognition. Binding of hSRY-HMG to its specific target site occurs exclusively in the minor groove and induces a large conformational change in the DNA. The DNA in the complex has an overall 70 degrees-80 degrees bend and is helically unwound relative to classical A- and B-DNA. The structure of the complex reveals the origin of sequence-specific binding within the HMG-1/HMG-2 family and provides a framework for understanding the effects of point mutations that cause 46X, Y sex reversal at the atomic level.

Title: Modular peptide recognition domains in eukaryotic signaling (review, #98 of > 20000 Oct 2005)

Source: ANNUAL REVIEW OF BIOPHYSICS AND BIOMOLECULAR STRUCTURE 26: 259-288 1997

Cited References: 104 Times Cited: 239

Abstract: A characteristic feature of cellular signal transduction pathways in eukaryotes is the separation of catalysis from target recognition. Several modular domains that recognize short peptide sequences and target signaling proteins to these sequences have been identified. The structural bases of the specificities of recognition by SH2, SH3, and PTB domains have been elucidated by X-ray crystallography and NMR, and these results are reviewed here. In addition, the mechanism of cooperative interactions between these domains is discussed.

Title: Structural changes linked to proton translocation by subunit c of the ATP synthase (#195 of > 20000 Oct 05)

Source: NATURE 402 (6759): 263-268 NOV 18 1999

Cited References: 50 Times Cited: 179

Abstract: F1F0 ATP synthases use a transmembrane proton gradient to drive the synthesis of cellular ATP. The structure of the cytosolic F-1 portion of the enzyme and the basic mechanism of ATP hydrolysis by F-1 are now well established, but how proton translocation through the transmembrane F-0 portion drives these catalytic changes is less clear. Here we describe the structural changes in the proton-translocating F-0 subunit c that are induced by deprotonating the specific aspartic acid involved in proton transport. conformational changes between the protonated and deprotonated forms of subunit c provide the structural basis for an explicit mechanism to explain coupling of proton translocation by F-0 to the rotation of subunits within the core of F-1. Rotation of these subunits within F-1 causes the catalytic conformational changes in the active sites of F-1 that result in ATP synthesis.

Title: SOLUTION STRUCTURE OF THE HUMAN TELOMERIC REPEAT D[AG(3)(T(2)AG(3))3] G-TETRAPLEX (#196 of > 20000 Oct 05)

Source: STRUCTURE 1 (4): 263-282 DEC 15 1993

Cited References: 55 Times Cited: 179

Abstract: Background: Repeats of G, sequences are detected as single strand overhangs at the ends of eukaryotic chromosomes together with associated binding proteins. Such telomere sequences have been implicated in the replication and maintenance of chromosomal termini. They may also mediate chromosomal organization and association during meiosis and mitosis.

Results: We have determined the three-dimensional solution structure of the human telomere sequence, d[AG(3)(T(2)AG(3))(3)] in Na+-containing solution using a combined NMR, distance geometry and molecular dynamics approach (including relaxation matrix refinement). The sequence, which contains four AG(3) repeats, folds intramolecularly into a G-tetraplex stabilized by three stacked G-tetrads which are connected by two lateral loops and a central diagonal loop. Of the four grooves chat are formed, one is wide, two are of medium width and one is narrow. The alignment of adjacent G-G-G segments in parallel generates the two grooves of medium width whilst the antiparallel arrangement results in one wide and one narrow groove. Three of the four adenines stack on top of adjacent G-tetrads while the majority of the thymines sample multiple conformations.

Conclusions: The availability of the d[AG(3)(T(2)AG(3))(3)] solution structure containing four AG(3) human telomeric repeats should permit the rational design of ligands that recognize and bind with specificity and affinity to the individual grooves of the G-tetraplex, as well as to either end containing the diagonal and lateral loops. Such ligands could modulate the equilibrium between folded G-tetraplex structures and their unfolded extended counterparts.

Title: Solution structure of the proapoptotic molecule BID: A structural basis for apoptotic agonists and antagonists (#226 of > 20000 Oct 05)

Author(s): McDonnell JM, Fushman D, Milliman CL, Korsmeyer SJ, Cowburn D

Source: CELL 96 (5): 625-634 MAR 5 1999

Cited References: 66 Times Cited: 169

Abstract: Members of the BCL2 family of proteins are key regulators of programmed cell death, acting either as apoptotic agonists or antagonists. Here we describe the solution structure of BID, presenting the structure of a proapoptotic BCL2 family member. An analysis of sequence/structure of BCL2 family members allows us to define a structural superfamily, which has implications for general mechanisms for regulating proapoptotic activity. It appears two criteria must be met for proapoptotic function within the BCL2 family: targeting of molecules to intracellular membranes, and exposure of the BH3 death domain. BID's activity is regulated by a Caspase 8-mediated cleavage event, exposing the BH3 domain and significantly changing the surface charge and hydrophobicity, resulting in a change of cellular localization.

Title: Nuclear magnetic resonance studies of biopolymer dynamics (#235 of > 20000 Oct 05)

Source: JOURNAL OF PHYSICAL CHEMISTRY 100 (31): 13293-13310 AUG 1 1996

Cited References: 190 Times Cited: 166

Abstract: NMR spectroscopy is a powerful approach for quantitating molecular conformational dynamics at multiple atomic sites and over multiple time scales. Extensive studies by solution and solid-state NMR spectroscopy of spin relaxation and line shapes in biological macromolecules have been performed in order to characterize the amplitudes, time scales, and energetics of intramolecular conformational modes and to elucidate the relationships between conformational dynamics, structure, and function. This review describes NMR spectroscopic methods for investigation of conformational dynamics together with theoretical descriptions appropriate for interpretation and simulation of the techniques, surveys the range of results available from solution and solid state NMR studies of proteins and other biomolecules, and identifies opportunities for further individual and collaborative development of solution and solid state NMR techniques for characterizing the dynamical properties of biological macromolecules.

Title: BACKBONE DYNAMICS OF CALCIUM-LOADED CALBINDIN-D(9K) STUDIED BY 2-DIMENSIONAL PROTON-DETECTED N-15 NMR-SPECTROSCOPY (#292 of > 20000 Oct 05)

Source: BIOCHEMISTRY 31 (20): 4856-4866 MAY 26 1992

Cited References: 67 Times Cited: 162

Abstract: Backbone dynamics of calcium-loaded calbindin D9k have been investigated by two-dimensional proton-detected heteronuclear nuclear magnetic resonance spectroscopy, using a uniformly N-15 enriched protein sample. Spin-lattice relaxation rate constants, spin-spin relaxation rate constants, and steady-state {H-1}-N-15 nuclear Overhauser effects were determined for 71 of the 72 backbone amide N-15 nuclei. The relaxation parameters were analyzed using a model-free formalism that incorporates the overall rotational correlation time of the molecule, and a generalized order parameter (S2) and an effective internal correlation time for each amide group. Calbindin D9k contains two helix-loop-helix motifs joined by a linker loop at one end of the protein and a beta-type interaction between the two calcium-binding loops at the other end. The amplitude of motions for the calcium-binding loops and the helices are similar, as judged from the average S2 values of 0.83 +/- 0.05 and 0.85 +/- 0.04, respectively. The linker region joining the two calcium-binding subdomains of the molecule has a significantly higher flexibility, as indicated by a substantially lower average S2 value of 0.59 +/- 0.23. For residues in the linker loop and at the C-terminus, the order parameter is further decomposed into separate order parameters for motional processes on two distinct time scales. The effective correlation times are significantly longer for helices I and IV than for helices II and III or for the calcium-binding loops. Residue by residue comparisons reveal correlations of the order parameters with both the crystallographic B-factors and amide proton exchange rates, despite vast differences in the time scales to which these properties are sensitive. The order parameters are also utilized to distinguish regions of the NMR-derived three-dimensional structure of calbindin D9k that are poorly defined due to inherently high flexibility, from poorly defined regions with average flexibility but a low density of structural constraints.

Title: PROTEIN DYNAMICS STUDIED BY ROTATING FRAME N-15 SPIN RELAXATION-TIMES (#276 of 20000, Oct 05)

Source: JOURNAL OF BIOMOLECULAR NMR 3 (2): 151-164 MAR 1993

Cited References: 48 Times Cited: 153

Abstract: Conformational rate processes in aqueous solutions of uniformly N-15-labeled pancreatic trypsin inhibitor (BPTI) at 36-degrees-C were investigated by measuring the rotating frame relaxation times of the backbone N-15 spins as a function of the spin-lock power, Two different intramolecular exchange processes were identified. A first local rate process involved the residues Cys38 and Arg39, had a correlation time of about 1.3 ms, and was related to isomerization of the chirality of the disulfide bond Cys14-Cys38. A second, faster motional mode was superimposed on the disulfide bond isomerization and was tentatively attributed to local segmental motions in the polypeptide sequence - Cys14 - Ala15 - Lys16 -. The correlation time for the overall rotational tumbling of the protein was found to be 2 ns, using the assumption that relaxation is dominated by dipolar coupling and chemical shift anistropy modulated by isotropic molecular reorientation.

Title: Solution structure of the transmembrane H+-transporting subunit c of the F1F0 ATP synthase (#283 of >20000 Oct 05)

Source: BIOCHEMISTRY 37 (25): 8817-8824 JUN 23 1998

Cited References: 56 Times Cited: 151

Abstract: Subunit c is the H+-translocating component of the F1F0 ATP synthase complex. H+ transport is coupled to conformational changes that ultimately lead to ATP synthesis by the enzyme. The properties of the monomeric subunit in a single phase solution of chloroform-methanol - water (4:4:1) have been shown to mimic those of the protein in the native complex. Triple resonance NMR experiments were used to determine the complete structure of monomeric subunit c in this solvent mixture. The structure of the protein was defined by >2000 interproton distances, 64 (3)J(N alpha), and 43 hydrogen-bonding NMR-derived restraints. The root mean squared deviation for the backbone atoms of the two transmembrane helices was 0.63 Angstrom. The protein folds as a hairpin of two antiparallel helical segments, connected by a short structured loop. The conserved Arg41-Gln42-Pro43 form the top of this loop. The essential H+-transporting Asp61 residue is located at a slight break in the middle of the C-terminal helix, just prior to Pro64. The C-terminal helix changes direction by 30 +/- 5 degrees at the conserved Pro64. In its protonated form, the Asp61 lies in a cavity created by the absence of side chains at Gly23 and Gly27 in the N-terminal helix. The shape and charge distribution of the molecular surface of the monomeric protein suggest a packing arrangement for the oligomeric protein in the F-o complex, with the front face of one monomer packing favorably against the back face of a second monomer. The packing suggests that the proton (cation) binding site lies between packed pairs of adjacent subunit c.

NMR / Related techniques

Title: INTRAMOLECULAR MOTIONS OF A ZINC FINGER DNA-BINDING DOMAIN FROM XFIN CHARACTERIZED BY PROTON-DETECTED NATURAL ABUNDANCE C-12 HETERONUCLEAR NMR-SPECTROSCOPY (#28)

Source: JOURNAL OF THE AMERICAN CHEMICAL SOCIETY 113 (12): 4371-4380 JUN 5 1991

Cited References: 91 Times Cited: 384

Abstract: The zinc finger DNA-binding domain Xfin-31 is a 25-residue peptide that binds a single zinc atom and forms a compact globular structure in solution. To characterize the intramolecular dynamics of Xfin-31, the C-13 spin-lattice and spin-spin relaxation rate constants and the {H-1}-C-13 nuclear Overhauser effect (NOE) enhancements have been measured for the backbone and side chain methine carbons by two-dimensional proton-detected heteronuclear NMR spectroscopy at a C-13 Larmor frequency of 125 MHz and natural C-13 abundance. The relaxation rate constants and the NOE enhancements have been analyzed by using a model-free formalism that depends on the overall rotational correlation time of the molecule, tau-m, the order parameter S, and effective internal correlation time, tau-e, for each methine carbon. The optimized global value of tau-m is 1.88 +/- 0.02 ns. The backbone C-alpha carbons are grouped into four categories based on the values of the order parameters: the N-terminal residue Tyr1 with S2 = 0.73 +/- 0.04; the C-terminal residues Lys24 and Asn25 with S2 < 0.5; residues Phe10-Lysl3 with an average S2 = 0.77 +/- 0.03; and the remainder of the backbone carbon nuclei with an average S2 = 0.89 +/- 0.05. For the side chain C-beta of Val11 and Val22 and the C-gamma of Leu5, the values of S2 are 0.62 +/- 0.03, 0.66 +/- 0.04, and 0.47 +/- 0.03, respectively. Estimates of tau-e could be obtained for 13 of the backbone and 3 of the side chain methine carbons. Excluding the terminal residues, the average value of tau-e for the backbone carbon nuclei was 34 +/- 16 ps. With the exception of the terminal residues, the motions of the backbone carbon nuclei of Xfin-31 are highly restricted. Residues 10-13, which form a turn between the beta-sheet and the helix present in the three-dimensional structure of Xfin-31, have a slightly higher mobility than the rest of the interior backbone, and the two residues at the C-terminus have considerable conformational flexibility. The side chains of the hydrophobic Val and Leu residues are more mobile than the backbone but are still significantly restricted, which indicates that Xfin-31 is compact despite its small size. Systematically large spin-spin relaxation rates for residues in the zinc binding site imply that conformational exchange may occur in this region on a time scale longer than the overall rotational correlation time.

Title: BACKBONE DYNAMICS OF ESCHERICHIA-COLI RIBONUCLEASE HI - CORRELATIONS WITH STRUCTURE AND FUNCTION IN AN ACTIVE ENZYME (#30)

Source: JOURNAL OF MOLECULAR BIOLOGY 246 (1): 144-163 FEB 10 1995

Cited References: 102 Times Cited: 379

Abstract: Ribonuclease H is an endonuclease that hydrolyzes the RNA moiety of RNA-DNA duplex molecules. Escherichia coli ribonuclease H is involved in DNA replication, and retroviral ribonuclease H is essential for reverse transcription of the viral genome. To characterize the intramolecular dynamical properties of E. coli ribonuclease H, spin-lattice relaxation rate constants, spin-spin relaxation rate constants and steady state nuclear Overhauser effects for the N-15 nuclear spins were measured by using proton-detected heteronuclear NMR spectroscopy; The relaxation data were analyzed by using a series of dynamical models in conjunction with a statistical model selection protocol. Ribonuclease H exhibits a complex array of dynamical features, most notably in the parallel beta-strands of the principal five-stranded beta-sheet, the coiled-coil helical interface, the active site, and the loop regions surrounding the active site. The dynamical properties are correlated with local structural environments of the N-15 spins and suggest possible relationships to the functional properties of ribonuclease H. Results for E. coli ribonuclease H are compared to previously reported results for the human immunodeficiancy virus type 1 ribonuclease H domain of reverse transcriptase.

Title: SUPPRESSION OF THE EFFECTS OF CROSS-CORRELATION BETWEEN DIPOLAR AND ANISOTROPIC CHEMICAL-SHIFT RELAXATION MECHANISMS IN THE MEASUREMENT OF SPIN SPIN RELAXATION RATES (#90)

Source: MOLECULAR PHYSICS 75 (3): 699-711 FEB 20 1992

Cited References: 53 Times Cited: 220

Abstract: Cross correlation between dipolar and anisotropic chemical shift relaxation mechanisms complicates measurements of heteronuclear spin-spin relaxation rate constants by the Carr-Purcell-Meiboom-Gill (CPMG) technique if the magnitudes of the chemical shift anisotropy and the dipolar interaction are comparable. Experimental schemes are described that attenuate the effects of cross correlation and permit accurate measurements of spin-spin relaxation rate constants for heteronuclei with significant chemical shift anisotropies. The theoretical analysis is confirmed by measurements of N-15 and C-13 spin-spin relaxation in a peptide. Application of 180-degrees pulses to the protons directly attached to the heteronuclei in synchrony with the even echoes of the heteronuclear spins yields more accurate results than continuous irradiation of the protons with a composite pulse decoupling sequence or application of a single 180-degrees pulse to the protons in the middle of the CPMG pulse train.

Title: LONG-RANGE HYDROGEN-BOND MEDIATED EFFECTS IN PEPTIDES - N-15 NMR-STUDY OF GRAMICIDIN-S IN WATER AND ORGANIC-SOLVENTS (#108)

Source: JOURNAL OF THE AMERICAN CHEMICAL SOCIETY 106 (7): 1939-1941 1984

Cited References: 20 Times Cited: 208

Title: Structural and dynamic characterization of partially folded states of apomyoglobin and implications for protein folding (#127)

Source: NATURE STRUCTURAL BIOLOGY 5 (2): 148-155 FEB 1998

Cited References: 57 Times Cited: 191

Abstract: The structure and dynamics of two partially folded states of apomyoglobin have been characterized at equilibrium using multi-dimensional NMR spectroscopy. Residue-specific measurements of chemical shift and internal dynamics in these states and in the native apoprotein and holoprotein indicate progressive accumulation of secondary structure and increasing restriction of backbone dynamics as the chain collapses to form increasingly compact states. Under weakly folding conditions, the polypeptide fluctuates between unfolded states and local elements of structure that become extended and stabilized as the chain becomes more compact. These results provide a detailed model for molecular events that are likely to occur during folding of myoglobin.

The 20 Most-Frequently-Cited Chemistry in PNAS as of 01/02/2005 - 10/02/2005 -- updated monthly

Most-cited rankings are recalculated at the beginning of the month. Rankings are based on citations to articles on this journal site from articles in HighWire-hosted journals.

http://www.nysbc.net/library//20021103.bak/20021103.bak/new.pdf/10359756.pdf Rank 1. Y. Oda, K. Huang, F. R. Cross, D. Cowburn, B. T. Chait Accurate quantitation of protein expression and site-specific phosphorylation PNAS Jun 08, 1999 96: 6591-6596.

Papers with high citation statistics associated with NYSBC investigators

NMR/ Structural Biology

Title: Structure and ligand of a histone acetyltransferase bromodomain ( #64 of >20,000 related Oct 2005)

Author(s): Dhalluin C, Carlson JE, Zeng L, He C, Aggarwal AK, Zhou MM

Source: NATURE 399 (6735): 491-496 JUN 3 1999

Cited References: 29 Times Cited: 308

Abstract: Histone acetylation is important in chromatin remodelling and gene activation(1-4). Nearly all known histone-acetyltransferase (HAT)-associated transcriptional co-activators contain bromodomains, which are similar to 110-amino-acid modules found in many chromatin-associated proteins(5-9). Despite the wide occurrence of these bromodomains, their three-dimensional structure and binding partners remain unknown. Here we report the solution structure of the bromodomain of the HAT co-activator P/CAF (p300/CBP-associated factor)(10,11). The structure reveals an unusual left-handed up-and-down four-helix bundle. In addition, we show by a combination of structural and site-directed mutagenesis studies that bromodomains can interact specifically with acetylated lysine, making them the first known protein modules to do so, The nature of the recognition of acetyl-lysine by the P/CAF bromodomain is similar to that of acetyl-CoA by histone acetyltransferase. Thus, the bromodomain is functionally linked to the HAT activity of co-activators in the regulation of gene transcription.

Title: MOLECULAR-BASIS OF HUMAN 46X,Y SEX REVERSAL REVEALED FROM THE 3-DIMENSIONAL SOLUTION STRUCTURE OF THE HUMAN SRY-DNA COMPLEX (#69 of > 20000 Oct 2005)

Source: CELL 81 (5): 705-714 JUN 2 1995

Cited References: 49 Times Cited: 293

Abstract: The solution structure of the specific complex between the high mobility group (HMG) domain of SRY (hSRY-HMG), the protein encoded by the human testis-determining gene, and its DNA target site in the promoter of the Mullerian inhibitory substance gene has been determined by multidimensional NMR spectroscopy. hSRY-HMG has a twisted L shape that presents a concave surface (made up of three helices and the N- and C-terminal strands) to the DNA for sequence-specific recognition. Binding of hSRY-HMG to its specific target site occurs exclusively in the minor groove and induces a large conformational change in the DNA. The DNA in the complex has an overall 70 degrees-80 degrees bend and is helically unwound relative to classical A- and B-DNA. The structure of the complex reveals the origin of sequence-specific binding within the HMG-1/HMG-2 family and provides a framework for understanding the effects of point mutations that cause 46X, Y sex reversal at the atomic level.

Title: Modular peptide recognition domains in eukaryotic signaling (review, #98 of > 20000 Oct 2005)

Source: ANNUAL REVIEW OF BIOPHYSICS AND BIOMOLECULAR STRUCTURE 26: 259-288 1997

Cited References: 104 Times Cited: 239

Abstract: A characteristic feature of cellular signal transduction pathways in eukaryotes is the separation of catalysis from target recognition. Several modular domains that recognize short peptide sequences and target signaling proteins to these sequences have been identified. The structural bases of the specificities of recognition by SH2, SH3, and PTB domains have been elucidated by X-ray crystallography and NMR, and these results are reviewed here. In addition, the mechanism of cooperative interactions between these domains is discussed.

Title: Structural changes linked to proton translocation by subunit c of the ATP synthase (#195 of > 20000 Oct 05)

Source: NATURE 402 (6759): 263-268 NOV 18 1999

Cited References: 50 Times Cited: 179

Abstract: F1F0 ATP synthases use a transmembrane proton gradient to drive the synthesis of cellular ATP. The structure of the cytosolic F-1 portion of the enzyme and the basic mechanism of ATP hydrolysis by F-1 are now well established, but how proton translocation through the transmembrane F-0 portion drives these catalytic changes is less clear. Here we describe the structural changes in the proton-translocating F-0 subunit c that are induced by deprotonating the specific aspartic acid involved in proton transport. conformational changes between the protonated and deprotonated forms of subunit c provide the structural basis for an explicit mechanism to explain coupling of proton translocation by F-0 to the rotation of subunits within the core of F-1. Rotation of these subunits within F-1 causes the catalytic conformational changes in the active sites of F-1 that result in ATP synthesis.

Title: SOLUTION STRUCTURE OF THE HUMAN TELOMERIC REPEAT D[AG(3)(T(2)AG(3))3] G-TETRAPLEX (#196 of > 20000 Oct 05)

Source: STRUCTURE 1 (4): 263-282 DEC 15 1993

Cited References: 55 Times Cited: 179

Abstract: Background: Repeats of G, sequences are detected as single strand overhangs at the ends of eukaryotic chromosomes together with associated binding proteins. Such telomere sequences have been implicated in the replication and maintenance of chromosomal termini. They may also mediate chromosomal organization and association during meiosis and mitosis.

Results: We have determined the three-dimensional solution structure of the human telomere sequence, d[AG(3)(T(2)AG(3))(3)] in Na+-containing solution using a combined NMR, distance geometry and molecular dynamics approach (including relaxation matrix refinement). The sequence, which contains four AG(3) repeats, folds intramolecularly into a G-tetraplex stabilized by three stacked G-tetrads which are connected by two lateral loops and a central diagonal loop. Of the four grooves chat are formed, one is wide, two are of medium width and one is narrow. The alignment of adjacent G-G-G segments in parallel generates the two grooves of medium width whilst the antiparallel arrangement results in one wide and one narrow groove. Three of the four adenines stack on top of adjacent G-tetrads while the majority of the thymines sample multiple conformations.

Conclusions: The availability of the d[AG(3)(T(2)AG(3))(3)] solution structure containing four AG(3) human telomeric repeats should permit the rational design of ligands that recognize and bind with specificity and affinity to the individual grooves of the G-tetraplex, as well as to either end containing the diagonal and lateral loops. Such ligands could modulate the equilibrium between folded G-tetraplex structures and their unfolded extended counterparts.

Title: Solution structure of the proapoptotic molecule BID: A structural basis for apoptotic agonists and antagonists (#226 of > 20000 Oct 05)

Author(s): McDonnell JM, Fushman D, Milliman CL, Korsmeyer SJ, Cowburn D

Source: CELL 96 (5): 625-634 MAR 5 1999

Cited References: 66 Times Cited: 169

Abstract: Members of the BCL2 family of proteins are key regulators of programmed cell death, acting either as apoptotic agonists or antagonists. Here we describe the solution structure of BID, presenting the structure of a proapoptotic BCL2 family member. An analysis of sequence/structure of BCL2 family members allows us to define a structural superfamily, which has implications for general mechanisms for regulating proapoptotic activity. It appears two criteria must be met for proapoptotic function within the BCL2 family: targeting of molecules to intracellular membranes, and exposure of the BH3 death domain. BID's activity is regulated by a Caspase 8-mediated cleavage event, exposing the BH3 domain and significantly changing the surface charge and hydrophobicity, resulting in a change of cellular localization.

Title: Nuclear magnetic resonance studies of biopolymer dynamics (#235 of > 20000 Oct 05)

Source: JOURNAL OF PHYSICAL CHEMISTRY 100 (31): 13293-13310 AUG 1 1996

Cited References: 190 Times Cited: 166

Abstract: NMR spectroscopy is a powerful approach for quantitating molecular conformational dynamics at multiple atomic sites and over multiple time scales. Extensive studies by solution and solid-state NMR spectroscopy of spin relaxation and line shapes in biological macromolecules have been performed in order to characterize the amplitudes, time scales, and energetics of intramolecular conformational modes and to elucidate the relationships between conformational dynamics, structure, and function. This review describes NMR spectroscopic methods for investigation of conformational dynamics together with theoretical descriptions appropriate for interpretation and simulation of the techniques, surveys the range of results available from solution and solid state NMR studies of proteins and other biomolecules, and identifies opportunities for further individual and collaborative development of solution and solid state NMR techniques for characterizing the dynamical properties of biological macromolecules.

Title: BACKBONE DYNAMICS OF CALCIUM-LOADED CALBINDIN-D(9K) STUDIED BY 2-DIMENSIONAL PROTON-DETECTED N-15 NMR-SPECTROSCOPY (#292 of > 20000 Oct 05)

Source: BIOCHEMISTRY 31 (20): 4856-4866 MAY 26 1992

Cited References: 67 Times Cited: 162

Abstract: Backbone dynamics of calcium-loaded calbindin D9k have been investigated by two-dimensional proton-detected heteronuclear nuclear magnetic resonance spectroscopy, using a uniformly N-15 enriched protein sample. Spin-lattice relaxation rate constants, spin-spin relaxation rate constants, and steady-state {H-1}-N-15 nuclear Overhauser effects were determined for 71 of the 72 backbone amide N-15 nuclei. The relaxation parameters were analyzed using a model-free formalism that incorporates the overall rotational correlation time of the molecule, and a generalized order parameter (S2) and an effective internal correlation time for each amide group. Calbindin D9k contains two helix-loop-helix motifs joined by a linker loop at one end of the protein and a beta-type interaction between the two calcium-binding loops at the other end. The amplitude of motions for the calcium-binding loops and the helices are similar, as judged from the average S2 values of 0.83 +/- 0.05 and 0.85 +/- 0.04, respectively. The linker region joining the two calcium-binding subdomains of the molecule has a significantly higher flexibility, as indicated by a substantially lower average S2 value of 0.59 +/- 0.23. For residues in the linker loop and at the C-terminus, the order parameter is further decomposed into separate order parameters for motional processes on two distinct time scales. The effective correlation times are significantly longer for helices I and IV than for helices II and III or for the calcium-binding loops. Residue by residue comparisons reveal correlations of the order parameters with both the crystallographic B-factors and amide proton exchange rates, despite vast differences in the time scales to which these properties are sensitive. The order parameters are also utilized to distinguish regions of the NMR-derived three-dimensional structure of calbindin D9k that are poorly defined due to inherently high flexibility, from poorly defined regions with average flexibility but a low density of structural constraints.

Title: PROTEIN DYNAMICS STUDIED BY ROTATING FRAME N-15 SPIN RELAXATION-TIMES (#276 of 20000, Oct 05)

Source: JOURNAL OF BIOMOLECULAR NMR 3 (2): 151-164 MAR 1993

Cited References: 48 Times Cited: 153

Abstract: Conformational rate processes in aqueous solutions of uniformly N-15-labeled pancreatic trypsin inhibitor (BPTI) at 36-degrees-C were investigated by measuring the rotating frame relaxation times of the backbone N-15 spins as a function of the spin-lock power, Two different intramolecular exchange processes were identified. A first local rate process involved the residues Cys38 and Arg39, had a correlation time of about 1.3 ms, and was related to isomerization of the chirality of the disulfide bond Cys14-Cys38. A second, faster motional mode was superimposed on the disulfide bond isomerization and was tentatively attributed to local segmental motions in the polypeptide sequence - Cys14 - Ala15 - Lys16 -. The correlation time for the overall rotational tumbling of the protein was found to be 2 ns, using the assumption that relaxation is dominated by dipolar coupling and chemical shift anistropy modulated by isotropic molecular reorientation.

Title: Solution structure of the transmembrane H+-transporting subunit c of the F1F0 ATP synthase (#283 of >20000 Oct 05)

Source: BIOCHEMISTRY 37 (25): 8817-8824 JUN 23 1998

Cited References: 56 Times Cited: 151

Abstract: Subunit c is the H+-translocating component of the F1F0 ATP synthase complex. H+ transport is coupled to conformational changes that ultimately lead to ATP synthesis by the enzyme. The properties of the monomeric subunit in a single phase solution of chloroform-methanol - water (4:4:1) have been shown to mimic those of the protein in the native complex. Triple resonance NMR experiments were used to determine the complete structure of monomeric subunit c in this solvent mixture. The structure of the protein was defined by >2000 interproton distances, 64 (3)J(N alpha), and 43 hydrogen-bonding NMR-derived restraints. The root mean squared deviation for the backbone atoms of the two transmembrane helices was 0.63 Angstrom. The protein folds as a hairpin of two antiparallel helical segments, connected by a short structured loop. The conserved Arg41-Gln42-Pro43 form the top of this loop. The essential H+-transporting Asp61 residue is located at a slight break in the middle of the C-terminal helix, just prior to Pro64. The C-terminal helix changes direction by 30 +/- 5 degrees at the conserved Pro64. In its protonated form, the Asp61 lies in a cavity created by the absence of side chains at Gly23 and Gly27 in the N-terminal helix. The shape and charge distribution of the molecular surface of the monomeric protein suggest a packing arrangement for the oligomeric protein in the F-o complex, with the front face of one monomer packing favorably against the back face of a second monomer. The packing suggests that the proton (cation) binding site lies between packed pairs of adjacent subunit c.

NMR / Related techniques

Title: INTRAMOLECULAR MOTIONS OF A ZINC FINGER DNA-BINDING DOMAIN FROM XFIN CHARACTERIZED BY PROTON-DETECTED NATURAL ABUNDANCE C-12 HETERONUCLEAR NMR-SPECTROSCOPY (#28)

Source: JOURNAL OF THE AMERICAN CHEMICAL SOCIETY 113 (12): 4371-4380 JUN 5 1991

Cited References: 91 Times Cited: 384

Abstract: The zinc finger DNA-binding domain Xfin-31 is a 25-residue peptide that binds a single zinc atom and forms a compact globular structure in solution. To characterize the intramolecular dynamics of Xfin-31, the C-13 spin-lattice and spin-spin relaxation rate constants and the {H-1}-C-13 nuclear Overhauser effect (NOE) enhancements have been measured for the backbone and side chain methine carbons by two-dimensional proton-detected heteronuclear NMR spectroscopy at a C-13 Larmor frequency of 125 MHz and natural C-13 abundance. The relaxation rate constants and the NOE enhancements have been analyzed by using a model-free formalism that depends on the overall rotational correlation time of the molecule, tau-m, the order parameter S, and effective internal correlation time, tau-e, for each methine carbon. The optimized global value of tau-m is 1.88 +/- 0.02 ns. The backbone C-alpha carbons are grouped into four categories based on the values of the order parameters: the N-terminal residue Tyr1 with S2 = 0.73 +/- 0.04; the C-terminal residues Lys24 and Asn25 with S2 < 0.5; residues Phe10-Lysl3 with an average S2 = 0.77 +/- 0.03; and the remainder of the backbone carbon nuclei with an average S2 = 0.89 +/- 0.05. For the side chain C-beta of Val11 and Val22 and the C-gamma of Leu5, the values of S2 are 0.62 +/- 0.03, 0.66 +/- 0.04, and 0.47 +/- 0.03, respectively. Estimates of tau-e could be obtained for 13 of the backbone and 3 of the side chain methine carbons. Excluding the terminal residues, the average value of tau-e for the backbone carbon nuclei was 34 +/- 16 ps. With the exception of the terminal residues, the motions of the backbone carbon nuclei of Xfin-31 are highly restricted. Residues 10-13, which form a turn between the beta-sheet and the helix present in the three-dimensional structure of Xfin-31, have a slightly higher mobility than the rest of the interior backbone, and the two residues at the C-terminus have considerable conformational flexibility. The side chains of the hydrophobic Val and Leu residues are more mobile than the backbone but are still significantly restricted, which indicates that Xfin-31 is compact despite its small size. Systematically large spin-spin relaxation rates for residues in the zinc binding site imply that conformational exchange may occur in this region on a time scale longer than the overall rotational correlation time.

Title: BACKBONE DYNAMICS OF ESCHERICHIA-COLI RIBONUCLEASE HI - CORRELATIONS WITH STRUCTURE AND FUNCTION IN AN ACTIVE ENZYME (#30)

Source: JOURNAL OF MOLECULAR BIOLOGY 246 (1): 144-163 FEB 10 1995

Cited References: 102 Times Cited: 379

Abstract: Ribonuclease H is an endonuclease that hydrolyzes the RNA moiety of RNA-DNA duplex molecules. Escherichia coli ribonuclease H is involved in DNA replication, and retroviral ribonuclease H is essential for reverse transcription of the viral genome. To characterize the intramolecular dynamical properties of E. coli ribonuclease H, spin-lattice relaxation rate constants, spin-spin relaxation rate constants and steady state nuclear Overhauser effects for the N-15 nuclear spins were measured by using proton-detected heteronuclear NMR spectroscopy; The relaxation data were analyzed by using a series of dynamical models in conjunction with a statistical model selection protocol. Ribonuclease H exhibits a complex array of dynamical features, most notably in the parallel beta-strands of the principal five-stranded beta-sheet, the coiled-coil helical interface, the active site, and the loop regions surrounding the active site. The dynamical properties are correlated with local structural environments of the N-15 spins and suggest possible relationships to the functional properties of ribonuclease H. Results for E. coli ribonuclease H are compared to previously reported results for the human immunodeficiancy virus type 1 ribonuclease H domain of reverse transcriptase.

Title: SUPPRESSION OF THE EFFECTS OF CROSS-CORRELATION BETWEEN DIPOLAR AND ANISOTROPIC CHEMICAL-SHIFT RELAXATION MECHANISMS IN THE MEASUREMENT OF SPIN SPIN RELAXATION RATES (#90)

Source: MOLECULAR PHYSICS 75 (3): 699-711 FEB 20 1992

Cited References: 53 Times Cited: 220

Abstract: Cross correlation between dipolar and anisotropic chemical shift relaxation mechanisms complicates measurements of heteronuclear spin-spin relaxation rate constants by the Carr-Purcell-Meiboom-Gill (CPMG) technique if the magnitudes of the chemical shift anisotropy and the dipolar interaction are comparable. Experimental schemes are described that attenuate the effects of cross correlation and permit accurate measurements of spin-spin relaxation rate constants for heteronuclei with significant chemical shift anisotropies. The theoretical analysis is confirmed by measurements of N-15 and C-13 spin-spin relaxation in a peptide. Application of 180-degrees pulses to the protons directly attached to the heteronuclei in synchrony with the even echoes of the heteronuclear spins yields more accurate results than continuous irradiation of the protons with a composite pulse decoupling sequence or application of a single 180-degrees pulse to the protons in the middle of the CPMG pulse train.

Title: LONG-RANGE HYDROGEN-BOND MEDIATED EFFECTS IN PEPTIDES - N-15 NMR-STUDY OF GRAMICIDIN-S IN WATER AND ORGANIC-SOLVENTS (#108)

Source: JOURNAL OF THE AMERICAN CHEMICAL SOCIETY 106 (7): 1939-1941 1984

Cited References: 20 Times Cited: 208

Title: Structural and dynamic characterization of partially folded states of apomyoglobin and implications for protein folding (#127)

Source: NATURE STRUCTURAL BIOLOGY 5 (2): 148-155 FEB 1998

Cited References: 57 Times Cited: 191

Abstract: The structure and dynamics of two partially folded states of apomyoglobin have been characterized at equilibrium using multi-dimensional NMR spectroscopy. Residue-specific measurements of chemical shift and internal dynamics in these states and in the native apoprotein and holoprotein indicate progressive accumulation of secondary structure and increasing restriction of backbone dynamics as the chain collapses to form increasingly compact states. Under weakly folding conditions, the polypeptide fluctuates between unfolded states and local elements of structure that become extended and stabilized as the chain becomes more compact. These results provide a detailed model for molecular events that are likely to occur during folding of myoglobin.

The 20 Most-Frequently-Cited Chemistry in PNAS as of 01/02/2005 - 10/02/2005 -- updated monthly

Most-cited rankings are recalculated at the beginning of the month. Rankings are based on citations to articles on this journal site from articles in HighWire-hosted journals.

http://www.nysbc.net/library//20021103.bak/20021103.bak/new.pdf/10359756.pdf Rank 1. Y. Oda, K. Huang, F. R. Cross, D. Cowburn, B. T. Chait Accurate quantitation of protein expression and site-specific phosphorylation PNAS Jun 08, 1999 96: 6591-6596.

http://www.nysbc.net/library//20021103.bak/20021103.bak/new.pdf/10359756.pdf Rank 1. Y. Oda, K. Huang, F. R. Cross, D. Cowburn, B. T. Chait Accurate quantitation of protein expression and site-specific phosphorylation PNAS Jun 08, 1999 96: 6591-6596.

Papers with high citation statistics associated with NYSBC

The 20 Most-Frequently-Cited Chemistry in PNAS as of 01/02/2005 - 5/02/2005 -- updated monthly

Most-cited rankings are recalculated at the beginning of the month. Rankings are based on citations to articles on this journal site from articles in HighWire-hosted journals.

http://www.nysbc.net/library//20021103.bak/20021103.bak/new.pdf/10359756.pdf Rank 1. Y. Oda, K. Huang, F. R. Cross, D. Cowburn, B. T. Chait Accurate quantitation of protein expression and site-specific phosphorylation PNAS Jun 08, 1999 96: 6591-6596.

Papers with high citation statistics associated with NYSBC

http://www.nysbc.net/library//20021103.bak/20021103.bak/new.pdf/10359756.pdf Rank 1. Y. Oda, K. Huang, F. R. Cross, D. Cowburn, B. T. Chait Accurate quantitation of protein expression and site-specific phosphorylation PNAS Jun 08, 1999 96: 6591-6596.

Papers with high citation statistics associated with NYSBC

http://www.nysbc.net/library//20021103.bak/20021103.bak/new.pdf/10359756.pdf Rank 1. Y. Oda, K. Huang, F. R. Cross, D. Cowburn, B. T. Chait Accurate quantitation of protein expression and site-specific phosphorylation PNAS Jun 08, 1999 96: 6591-6596.

Papers with high citation statistics associated with NYSBC

The 20 Most-Frequently-Cited Chemistry in PNAS as of 01/02/2005 -- updated monthly

Most-cited rankings are recalculated at the beginning of the month. Rankings are based on citations to articles on this journal site from articles in HighWire-hosted journals.

Papers with high citation statistics associated with NYSBC

The 20 Most-Frequently-Cited Chemistry in PNAS as of 01/02/2005 -- updated monthly

Most-cited rankings are recalculated at the beginning of the month. Rankings are based on citations to articles on this journal site from articles in HighWire-hosted journals.

1. Y. Oda, K. Huang, F. R. Cross, D. Cowburn, B. T. Chait Accurate quantitation of protein expression and site-specific phosphorylation PNAS Jun 08, 1999 96: 6591-6596. (In "Chemistry") Full Text