# Functional Determinants in G-Protein-Coupled Receptors

> **NIH NIH R01** · BAYLOR COLLEGE OF MEDICINE · 2022 · $472,000

## Abstract

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.

## Key facts

- **NIH application ID:** 10475232
- **Project number:** 5R01GM066099-17
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** OLIVIER LICHTARGE
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $472,000
- **Award type:** 5
- **Project period:** 2003-05-01 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10475232

## Citation

> US National Institutes of Health, RePORTER application 10475232, Functional Determinants in G-Protein-Coupled Receptors (5R01GM066099-17). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10475232. Licensed CC0.

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