Difference: ArthurPalmer (22 vs. 23)

• Name: Arthur Palmer
• Email: agp@nysbc.org
• Company Name: Columbia Univ. Medical Center
• Company URL: http://www.palmer.hs.columbia.edu
• Location: ColumbiaMedCenterOffice
• Address: Black Building 507, 630 West 168th Street New York, NY 10032
• Country: USA

Grants associated with NYSBC

GM59273

1. GM 59273 5/1/02-4/30/06; 5/1/06-4/30/10

Abstract: DESCRIPTION (provided by applicant): Recent developments, including those from the applicant laboratory, have opened new opportunities for investigation of dynamic processes on mu s-ms time scales using NMR spin relaxation measurements. Motions on these time scales reflect large-amplitude loop motions, relative motions between domains, collective "breathing" of protein cores, ligand-binding or oligomerization reactions, and overall folding-unfolding events. Such processes may be closely coupled, and in some instances rate-limiting, to biological functions such as molecular recognition, transitions along the catalytic cycle of enzymes, and inhibition or activation of proteins through intra-or inter-molecular protein-protein interactions. Mutations that perturb dynamical processes and conformational equilibria can be associated with significant pathology, including loss or gain of function and misfolding. The existence of large amplitude intra-molecular conformational changes in proteins have been inferred from comparison of equilibrium structures of a given protein in different crystal forms, a given protein in free and ligand-bound states, or sets of homologous proteins. However, only solution NMR spectroscopy can confirm the occurrence and determine the kinetic rates in the solution state of dynamic processes, at equilibrium and with atomic site resolution, in the absence of influences from intermolecular interactions in the solid state, and without potential complications introduced by non-native modifications necessary for other solution-state spectroscopic techniques. The proposed research has four primary objectives: (1) elucidation of the folding mechanism and description of the unfolded-state ensemble for the villin headpiece domain HP67; (2) identification of the mechanistic basis for coupling between agonist or antagonist binding and function of the ionotropic glutamate receptor GluR2 S1S2 ligand-binding domain; (3) assessment of the role of conformational mobility in catalysis by ornithine decarboxylase; and (4) development of novel experimental and theoretical methods for characterizing protein dynamics on mu s-ms time scales. Successful completion of these goals will enable applications to a wide range of protein systems of biological interest. Time-dependent structural changes underlie the normal function of proteins, and misfunction in genetic diseases, cancer, and other pathologies. The proposed research will measure these changes for three model protein systems involved in cellular structure, nerve transmission, and basic metabolism.

Public Health Relevance: This Public Health Relevance is not available.

Thesaurus Terms: protein acid, actin binding protein, active site, catalyst, chemical, conditioning, conformation, decarboxylase, dimer, enzyme, enzyme complex, gene mutation, genetics, glutamate receptor, insight, intermolecular interaction, ionization, isomerase, lead, ligand, magnetism, measurement, metabolism, method development, model, motivation, mutant, neoplasm /cancer, nerve, ornithine decarboxylase, pathology, phosphate, posttranslational modification, protein folding, protein protein interaction, pulmonary respiration, receptor expression, relaxation, role, solid state, solution, technology /technique development, trypsin inhibitor, ubiquitin

Institution: COLUMBIA UNIVERSITY HEALTH SCIENCES Columbia University Medical Center NEW YORK, NY 100323702 Fiscal Year: 2009 Department: BIOCHEM & MOLECULAR BIOPHYSICS Project Start: 01-MAY-1999 Project End: 30-APR-2010 ICD: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES IRG: ZRG1

GM50291

Grant Number: 2R01GM050291-12 PI Name: PALMER, ARTHUR G. PI Email: agp6@columbia.edu PI Title: PROFESSOR Project Title: Nuclear Magnetic Resonance Studies of Proteins

Abstract: DESCRIPTION (provided by applicant): Comprehensive experimental information on the essential contributions of intramolecular dynamics to biological functions of proteins is critical for biophysical theories of equilibrium properties, such as heat capacity and thermal stability; for mechanistic interpretations of kinetic processes, such as enzyme catalysis and ligand recognition; and for design of novel proteins and protein ligands, including pharmaceutical agents. This research project will use multidimensional NMR spectroscopy to address these fundamental issues. One long-term goal is to define the molecular determinants of stability and catalytic activity of the enzyme ribonuclease HI (RNase H) by comparing the structural, dynamical and enzymatic properties of homologous proteins derived from Escherichia coli and the extremely thermophilic bacterium Thermus thermophilus. The enzyme is distributed widely in prokaryotes and eukaryotes, and retroviral reverse transcriptase contains a C-terminal RNase H domain. Another long-term goal is to define the molecular determinants of ligand binding, including aspects of specificity, and allosterism, in DNA recognition by the yeast protein GCN4 and in nucleotide binding by the ATP-binding cassette (ABC) MJ1267 of the branched chain amino acid (LIV) transporter from Methanococcus jannaschii. GCN4 is the prototypical member of the bZip family of transcription activators. Motifs that recognize specific DNA sequences are ubiquitous components of proteins that regulate gene expression; consequently, explication of the molecular basis for recognition is critical for understanding normal biological function and pathology. GCN4 represents an example of induced fit molecular recognition through a disorder-order transition associated with DNA binding. The LIV transporter is a member of a diverse family of ABC transporters involved in numerous biological processes and diseases, including multidrug resistance and cystic fibrosis. ABC MJ1267 represents an example of selected-fit molecular recognition and allosteric transmission of conformational changes between remote sites in proteins.

Thesaurus Terms: bacterial protein, enzyme activity, intermolecular interaction, molecular dynamics, protein structure function, ribonuclease H, structural biology, thermostability adenosine diphosphate, adenosine triphosphate, biophysics, chemical kinetics, enzyme substrate complex, membrane transport protein, molecular site, nucleic acid, protein folding, species difference, temperature, transcription factor Archaea, Escherichia coli, nuclear magnetic resonance spectroscopy, site directed mutagenesis

Institution: COLUMBIA UNIVERSITY HEALTH SCIENCES PO Box 49 NEW YORK, NY 10032 Fiscal Year: 2005 Department: BIOCHEM & MOLECULAR BIOPHYSICS Project Start: 01-AUG-1994 Project End: 31-JUL-2009 ICD: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES IRG: MSFC

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