The long-term goal of this work is to rationally manipulate G protein-coupled receptor (GPCRs) activation with the hope to develop novel therapeutic approaches in this major family of transmembrane receptors and drug targets. Our hypothesis is that different GPCRs share common elements of their signal transduction mechanism. If so, it should be possible to compare and contrast their sequences to reveal functionally relevant amino acid variation patterns, some that are common to all receptors and indicative of shared mechanisms, and others that are unique to some branches of the family and indicative of ligand-specific mechanisms. This principle led to a general algorithm, called the Evolutionary Trace (ET) that correlates residue substitutions with evolutionary divergences and thus ranks the evolutionary importance of a protein's residues. It was shown, in the past funding period that ET could search protein structure for functional sites and their specificity determinants on a large-scale. Mutations guided to ET's top-ranked residues (so-called """"""""trace residues"""""""") repeatedly blocked, separated, mimicked, or rewired protein interactions in numerous experimental case studies in GPCRs and in other proteins. In parallel, high-throughput ET analyses suggested that trace residues have distinctive and quantifiable and proteome-wide properties in terms of structural clustering, biophysical interaction, and functional specificity. This proposal builds on these observations by pursuing three specific aims: 1. To redirect ligand binding in bioamine receptors. 2. To redesign ligand binding and dimerization in metabotropic glutamate receptors. 3. To identify transmembrane GPCR response modulators on a large scale. The outcome should reveal new aspects of the molecular basis of signaling in an important family of pharmaceutical targets. It will also link sequence and structure genomics databases to the molecular basis of function and to the rational re-design of protein interactions - key steps towards manipulating cellular pathways. It will benefit human health by providing new approaches to rational drug design and by enhancing the diagnostic value of SNP analysis and human genotyping.

Public Health Relevance

The few G protein coupled receptors that have been successfully targeted by drugs so far still provide the basis for nearly half of all current medications. The difficulty in creating medications against them is that we have limited knowledge of how they work. This proposal attempts to uncover the mechanisms of these proteins so that we can design new drugs that block their role in diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM066099-09
Application #
8134757
Study Section
Special Emphasis Panel (ZRG1-BCMB-B (02))
Program Officer
Dunsmore, Sarah
Project Start
2002-07-01
Project End
2014-08-31
Budget Start
2011-09-01
Budget End
2014-08-31
Support Year
9
Fiscal Year
2011
Total Cost
$440,309
Indirect Cost
Name
Baylor College of Medicine
Department
Genetics
Type
Schools of Medicine
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030
Chun, Yun Shin; Passot, Guillaume; Yamashita, Suguru et al. (2017) Deleterious Effect of RAS and Evolutionary High-risk TP53 Double Mutation in Colorectal Liver Metastases. Ann Surg :
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Xu, Qifang; Tang, Qingling; Katsonis, Panagiotis et al. (2017) Benchmarking predictions of allostery in liver pyruvate kinase in CAGI4. Hum Mutat 38:1123-1131
Schönegge, Anne-Marie; Gallion, Jonathan; Picard, Louis-Philippe et al. (2017) Evolutionary action and structural basis of the allosteric switch controlling ?2AR functional selectivity. Nat Commun 8:2169
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Gallion, Jonathan; Wilkins, Angela D; Lichtarge, Olivier (2017) HUMAN KINASES DISPLAY MUTATIONAL HOTSPOTS AT COGNATE POSITIONS WITHIN CANCER. Pac Symp Biocomput 22:414-425

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