Difference: KevinDalby (1 vs. 6)
Revision 619 Nov 2008 - Main.DavidCowburn
My Links
Personal PreferencesUncomment preferences variables to activate them (remove the #-sign). Help and details on preferences variables are available in TWikiPreferences.
Related Topics
Publicly available grant information Grant Number: 2R01GM059802-06A2 Project Title: ERK2: Structure, Function and Inhibition PI Information: Name Email Title DALBY, KEVIN N. dalby@mail.utexas.edu ASSOCIATE PROFESSOR Abstract: DESCRIPTION (provided by applicant): BRAF oncogenic mutations occur in approximately 8% of human cancers and lead to sustained activity of the Ser/Thr-specific protein kinases ERK1 and ERK2, which are critical mediators of cell entry into the S- phase of the human cell cycle. To begin to understand the principles governing substrate recognition and catalysis by ERK1/2, the structure and dynamics of the ERK27Ets1 (enzyme7substrate) complex will be determined in Aim 1, using an array of sophisticated NMR techniques. A semi-synthetic bisubstrate analog of transcription factor Elk-1, another substrate of ERK1/2, will be constructed to mimic phosphoryl transfer and analyzed in a similar manner. These studies will be complimented by X-ray crystal structure approaches. In Aim 2, potent and highly selective Targeting Molecules that block interactions between ERK1/2 and its protein ligands will be acquired by greatly increasing the side chain diversity within consensus binding sequences. The mechanism of action and specificity of these targeting molecules will be determined using enzyme kinetics and structural approaches. In Aim 3, the Targeting Molecules will be delivered into cells using protein transduction domains, and their efficacy determined with respect to their ability to inhibit Growth Factor-stimulated ERK1/2 activity and cell growth. Significantly, this multi-disciplined research program will provide potent and specific inhibitors of ERK1/2 for the first time and will allow ERK1/2 substrate-recruiting sites to be validated as potential drug targets for human cancers. The methodology developed herein will be rapidly applicable to other protein kinases, thereby potentially embracing many human diseases, and will provide the basis for future translational studies in pre-clinical mouse models. PUBLIC HEALTH RELEVANCE: The focus of this application is an enzyme called ERK2 whose activity is upregulated in a large number of human cancers. The proposed studies will provide detailed structural information on how this enzyme interacts with other cellular proteins. A new technique will be developed to rapidly identify cell-permeable molecules that can prevent ERK2 from binding other cellular proteins. This will provide validation of ERK2 as a drug target, in models of human disease, and provide the experimental basis for validating other members of the same enzyme family. The studies proposed will be of high significance and will benefit human health. Public Health Relevance: This Public Health Relevance is not available. Thesaurus Terms: There are no thesaurus terms on file for this project. Institution: UNIVERSITY OF TEXAS AUSTIN PO BOX 7726 AUSTIN, TX 78713 Fiscal Year: 2008 Department: MEDICINAL CHEMISTRY Project Start: 01-APR-2001 Project End: 31-JUL-2012 ICD: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES IRG: MSFE Subcontract to MarkGirvin ; collaboration also with RonnieGhose
| |||||||||||||||||||||||||||||||||||||||||
| Changed: | |||||||||||||||||||||||||||||||||||||||||
| < < |
| ||||||||||||||||||||||||||||||||||||||||
| > > |
| ||||||||||||||||||||||||||||||||||||||||
| |||||||||||||||||||||||||||||||||||||||||
Revision 518 Nov 2008 - Main.DavidCowburn
My Links
Personal PreferencesUncomment preferences variables to activate them (remove the #-sign). Help and details on preferences variables are available in TWikiPreferences.
Related Topics
Publicly available grant information Grant Number: 2R01GM059802-06A2 Project Title: ERK2: Structure, Function and Inhibition PI Information: Name Email Title DALBY, KEVIN N. dalby@mail.utexas.edu ASSOCIATE PROFESSOR Abstract: DESCRIPTION (provided by applicant): BRAF oncogenic mutations occur in approximately 8% of human cancers and lead to sustained activity of the Ser/Thr-specific protein kinases ERK1 and ERK2, which are critical mediators of cell entry into the S- phase of the human cell cycle. To begin to understand the principles governing substrate recognition and catalysis by ERK1/2, the structure and dynamics of the ERK27Ets1 (enzyme7substrate) complex will be determined in Aim 1, using an array of sophisticated NMR techniques. A semi-synthetic bisubstrate analog of transcription factor Elk-1, another substrate of ERK1/2, will be constructed to mimic phosphoryl transfer and analyzed in a similar manner. These studies will be complimented by X-ray crystal structure approaches. In Aim 2, potent and highly selective Targeting Molecules that block interactions between ERK1/2 and its protein ligands will be acquired by greatly increasing the side chain diversity within consensus binding sequences. The mechanism of action and specificity of these targeting molecules will be determined using enzyme kinetics and structural approaches. In Aim 3, the Targeting Molecules will be delivered into cells using protein transduction domains, and their efficacy determined with respect to their ability to inhibit Growth Factor-stimulated ERK1/2 activity and cell growth. Significantly, this multi-disciplined research program will provide potent and specific inhibitors of ERK1/2 for the first time and will allow ERK1/2 substrate-recruiting sites to be validated as potential drug targets for human cancers. The methodology developed herein will be rapidly applicable to other protein kinases, thereby potentially embracing many human diseases, and will provide the basis for future translational studies in pre-clinical mouse models. PUBLIC HEALTH RELEVANCE: The focus of this application is an enzyme called ERK2 whose activity is upregulated in a large number of human cancers. The proposed studies will provide detailed structural information on how this enzyme interacts with other cellular proteins. A new technique will be developed to rapidly identify cell-permeable molecules that can prevent ERK2 from binding other cellular proteins. This will provide validation of ERK2 as a drug target, in models of human disease, and provide the experimental basis for validating other members of the same enzyme family. The studies proposed will be of high significance and will benefit human health. Public Health Relevance: This Public Health Relevance is not available. Thesaurus Terms: There are no thesaurus terms on file for this project. Institution: UNIVERSITY OF TEXAS AUSTIN PO BOX 7726 AUSTIN, TX 78713 Fiscal Year: 2008 Department: MEDICINAL CHEMISTRY Project Start: 01-APR-2001 Project End: 31-JUL-2012 ICD: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES IRG: MSFE | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Changed: | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| < < | Subcontract to MarkGirvin | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| > > | Subcontract to MarkGirvin ; collaboration also with RonnieGhose | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Revision 418 Nov 2008 - Main.DavidCowburn
My Links
Personal PreferencesUncomment preferences variables to activate them (remove the #-sign). Help and details on preferences variables are available in TWikiPreferences.
Related Topics
Publicly available grant information Grant Number: 2R01GM059802-06A2 Project Title: ERK2: Structure, Function and Inhibition PI Information: Name Email Title DALBY, KEVIN N. dalby@mail.utexas.edu ASSOCIATE PROFESSOR Abstract: DESCRIPTION (provided by applicant): BRAF oncogenic mutations occur in approximately 8% of human cancers and lead to sustained activity of the Ser/Thr-specific protein kinases ERK1 and ERK2, which are critical mediators of cell entry into the S- phase of the human cell cycle. To begin to understand the principles governing substrate recognition and catalysis by ERK1/2, the structure and dynamics of the ERK27Ets1 (enzyme7substrate) complex will be determined in Aim 1, using an array of sophisticated NMR techniques. A semi-synthetic bisubstrate analog of transcription factor Elk-1, another substrate of ERK1/2, will be constructed to mimic phosphoryl transfer and analyzed in a similar manner. These studies will be complimented by X-ray crystal structure approaches. In Aim 2, potent and highly selective Targeting Molecules that block interactions between ERK1/2 and its protein ligands will be acquired by greatly increasing the side chain diversity within consensus binding sequences. The mechanism of action and specificity of these targeting molecules will be determined using enzyme kinetics and structural approaches. In Aim 3, the Targeting Molecules will be delivered into cells using protein transduction domains, and their efficacy determined with respect to their ability to inhibit Growth Factor-stimulated ERK1/2 activity and cell growth. Significantly, this multi-disciplined research program will provide potent and specific inhibitors of ERK1/2 for the first time and will allow ERK1/2 substrate-recruiting sites to be validated as potential drug targets for human cancers. The methodology developed herein will be rapidly applicable to other protein kinases, thereby potentially embracing many human diseases, and will provide the basis for future translational studies in pre-clinical mouse models. PUBLIC HEALTH RELEVANCE: The focus of this application is an enzyme called ERK2 whose activity is upregulated in a large number of human cancers. The proposed studies will provide detailed structural information on how this enzyme interacts with other cellular proteins. A new technique will be developed to rapidly identify cell-permeable molecules that can prevent ERK2 from binding other cellular proteins. This will provide validation of ERK2 as a drug target, in models of human disease, and provide the experimental basis for validating other members of the same enzyme family. The studies proposed will be of high significance and will benefit human health. Public Health Relevance: This Public Health Relevance is not available. Thesaurus Terms: There are no thesaurus terms on file for this project. Institution: UNIVERSITY OF TEXAS AUSTIN PO BOX 7726 AUSTIN, TX 78713 Fiscal Year: 2008 Department: MEDICINAL CHEMISTRY Project Start: 01-APR-2001 Project End: 31-JUL-2012 ICD: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES IRG: MSFE | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Added: | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| > > | Subcontract to MarkGirvin | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Revision 318 Nov 2008 - Main.DavidCowburn
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Deleted: | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| < < | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
My Links
Personal PreferencesUncomment preferences variables to activate them (remove the #-sign). Help and details on preferences variables are available in TWikiPreferences.
Related Topics
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Added: | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| > > | Publicly available grant information Grant Number: 2R01GM059802-06A2 Project Title: ERK2: Structure, Function and Inhibition PI Information: Name Email Title DALBY, KEVIN N. dalby@mail.utexas.edu ASSOCIATE PROFESSOR Abstract: DESCRIPTION (provided by applicant): BRAF oncogenic mutations occur in approximately 8% of human cancers and lead to sustained activity of the Ser/Thr-specific protein kinases ERK1 and ERK2, which are critical mediators of cell entry into the S- phase of the human cell cycle. To begin to understand the principles governing substrate recognition and catalysis by ERK1/2, the structure and dynamics of the ERK27Ets1 (enzyme7substrate) complex will be determined in Aim 1, using an array of sophisticated NMR techniques. A semi-synthetic bisubstrate analog of transcription factor Elk-1, another substrate of ERK1/2, will be constructed to mimic phosphoryl transfer and analyzed in a similar manner. These studies will be complimented by X-ray crystal structure approaches. In Aim 2, potent and highly selective Targeting Molecules that block interactions between ERK1/2 and its protein ligands will be acquired by greatly increasing the side chain diversity within consensus binding sequences. The mechanism of action and specificity of these targeting molecules will be determined using enzyme kinetics and structural approaches. In Aim 3, the Targeting Molecules will be delivered into cells using protein transduction domains, and their efficacy determined with respect to their ability to inhibit Growth Factor-stimulated ERK1/2 activity and cell growth. Significantly, this multi-disciplined research program will provide potent and specific inhibitors of ERK1/2 for the first time and will allow ERK1/2 substrate-recruiting sites to be validated as potential drug targets for human cancers. The methodology developed herein will be rapidly applicable to other protein kinases, thereby potentially embracing many human diseases, and will provide the basis for future translational studies in pre-clinical mouse models. PUBLIC HEALTH RELEVANCE: The focus of this application is an enzyme called ERK2 whose activity is upregulated in a large number of human cancers. The proposed studies will provide detailed structural information on how this enzyme interacts with other cellular proteins. A new technique will be developed to rapidly identify cell-permeable molecules that can prevent ERK2 from binding other cellular proteins. This will provide validation of ERK2 as a drug target, in models of human disease, and provide the experimental basis for validating other members of the same enzyme family. The studies proposed will be of high significance and will benefit human health. Public Health Relevance: This Public Health Relevance is not available. Thesaurus Terms: There are no thesaurus terms on file for this project. Institution: UNIVERSITY OF TEXAS AUSTIN PO BOX 7726 AUSTIN, TX 78713 Fiscal Year: 2008 Department: MEDICINAL CHEMISTRY Project Start: 01-APR-2001 Project End: 31-JUL-2012 ICD: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES IRG: MSFE | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Revision 218 Nov 2008 - Main.SherryllJones
| |||||||||||||
| Deleted: | |||||||||||||
| < < | |||||||||||||
My Links
Personal PreferencesUncomment preferences variables to activate them (remove the #-sign). Help and details on preferences variables are available in TWikiPreferences.
Related Topics
| |||||||||||||
| Changed: | |||||||||||||
| < < |
| ||||||||||||
| > > |
| ||||||||||||
| |||||||||||||
| Changed: | |||||||||||||
| < < |
| ||||||||||||
| > > |
| ||||||||||||
| |||||||||||||
| Changed: | |||||||||||||
| < < |
| ||||||||||||
| > > |
| ||||||||||||
| |||||||||||||
| Changed: | |||||||||||||
| < < |
| ||||||||||||
| > > |
| ||||||||||||
| |||||||||||||
| Changed: | |||||||||||||
| < < |
| ||||||||||||
| > > |
| ||||||||||||
| |||||||||||||
Revision 117 Nov 2008 - Main.TWikiRegistrationAgent
My Links
Personal PreferencesUncomment preferences variables to activate them (remove the #-sign). Help and details on preferences variables are available in TWikiPreferences.
Related Topics
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
View topic
| History: r6 < r5 < r4 < r3
| More topic actions...
Copyright © by the contributing authors. All material on this collaboration platform is the property of the contributing authors.
Ideas, requests, problems regarding this intranet, Send feedback
Ideas, requests, problems regarding this intranet, Send feedback