FUNCTIONAL DETERMINANTS OF G PROTEIN-COUPLED RECEPTORS PROJECT SUMMARY/ABSTRACT 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 evolutionary divergence patterns can reveal the roles that GPCR sequence positions play, individually or together, in order to mediate ligand binding, allosteric conformational switching, and finally ligand-biased activation of efferent signaling pathways, which can be G protein-dependent or independent. In the past funding period, computational analysis of such evolutionary patterns revealed: Intramolecular allosteric communication in the transmembrane domain of dopamine D2R receptor; Modular components of an allosteric switch controlling B2AR functional selectivity; A new non-canonical cAMP- independent signaling pathway in that same receptor; and Ligand specificity determinants in the extracellular domain of metabotropic glutamate receptors (MGluR). Technical progress led to: increased accuracy to assess the impact of coding mutations in proteins through a first-principle equation for the evolutionary variations of genotype and phenotype; The generalization of our analyses of evolutionary divergence to consider co-varying residues; and new methods to unravel complex simultaneous assay readouts to stratify drug effects on GPCRs. Together these and other data support new aims that combine biological and algorithmic goals: 1. To titrate mutationally the signaling bias of bioamine receptors. 2. To uncover allosteric mediators in metabotropic glutamate receptors. 3. To identify a systematic role of GPCR mutations in cancer. 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 function?key steps towards manipulating cellular pathways.

Public Health Relevance

FUNCTIONAL DETERMINANTS OF G PROTEIN-COUPLED RECEPTORS Narrative of the project G protein-coupled receptors account for nearly half of all current medications, yet so far relatively few have been successfully targeted by drugs. One of the difficulties is that we have limited knowledge of their mechanisms at a detailed level. This proposal attempts to uncover the mechanisms of these proteins so that in the longer term we can design new drugs that block their role in diseases, including in cancer.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM066099-15
Application #
9994912
Study Section
Biochemistry and Biophysics of Membranes Study Section (BBM)
Program Officer
Koduri, Sailaja
Project Start
2003-05-01
Project End
2023-08-31
Budget Start
2020-09-01
Budget End
2021-08-31
Support Year
15
Fiscal Year
2020
Total Cost
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
Suryavanshi, Santosh V; Jadhav, Shweta M; Anderson, Kody L et al. (2018) Human muscle-specific A-kinase anchoring protein polymorphisms modulate the susceptibility to cardiovascular diseases by altering cAMP/PKA signaling. Am J Physiol Heart Circ Physiol 315:H109-H121
Karamitri, Angeliki; Plouffe, Bianca; Bonnefond, Amélie et al. (2018) Type 2 diabetes-associated variants of the MT2 melatonin receptor affect distinct modes of signaling. Sci Signal 11:
Swings, Toon; Marciano, David C; Atri, Benu et al. (2018) CRISPR-FRT targets shared sites in a knock-out collection for off-the-shelf genome editing. Nat Commun 9:2231
Almannai, Mohammed; Wang, Julia; Dai, Hongzheng et al. (2018) FARS2 deficiency; new cases, review of clinical, biochemical, and molecular spectra, and variants interpretation based on structural, functional, and evolutionary significance. Mol Genet Metab 125:281-291
Lin, Chih-Hsu; Konecki, Daniel M; Liu, Meng et al. (2018) Multimodal Network Diffusion Predicts Future Disease-Gene-Chemical Associations. Bioinformatics :
Gennarino, Vincenzo A; Palmer, Elizabeth E; McDonell, Laura M et al. (2018) A Mild PUM1 Mutation Is Associated with Adult-Onset Ataxia, whereas Haploinsufficiency Causes Developmental Delay and Seizures. Cell 172:924-936.e11
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 :
Carraro, Marco; Minervini, Giovanni; Giollo, Manuel et al. (2017) Performance of in silico tools for the evaluation of p16INK4a (CDKN2A) variants in CAGI. Hum Mutat 38:1042-1050
Xu, Qifang; Tang, Qingling; Katsonis, Panagiotis et al. (2017) Benchmarking predictions of allostery in liver pyruvate kinase in CAGI4. Hum Mutat 38:1123-1131
Katsonis, Panagiotis; Lichtarge, Olivier (2017) Objective assessment of the evolutionary action equation for the fitness effect of missense mutations across CAGI-blinded contests. Hum Mutat 38:1072-1084

Showing the most recent 10 out of 89 publications