# Structural dynamics underlying GPCR-G protein selectivity

> **NIH NIH R01** · BECKMAN RESEARCH INSTITUTE/CITY OF HOPE · 2024 · $352,000

## Abstract

Summary:
Title: Structural dynamics underlying GPCR-G protein selectivity
Upon binding to agonists with different efficacies, G protein-coupled receptors (GPCRs) mediate
multiple signaling pathways by coupling to different subtypes of G proteins. Certain agonists exhibit
selectivity in their efficacy to specific G-protein signaling pathways. Such ligands provide precise
therapeutic benefits with fewer side effects as drugs compared to today's GPCR-targeted drugs. There
are very few selective ligands known for specific G-protein signaling pathways because designing such
agonists is a daunting experimental challenge. This is due to serious lack of understanding of how
GPCRs modulate their functional selectivity for their cognate G-protein when bound to different type of
agonists and in cells. In the past three years using a combination of multiscale molecular dynamics
(MD) method and genetically coded FRET sensors we have shown that GPCRs have latent intracellular
cavities that can reshape and couple to different G-proteins. By reengineering G-proteins and GPCRs
we have identified the hotspot residues in the GPCR-G-protein interface that serve as the “QR code” for
G-protein selective coupling by GPCRs. Although it is clear that allosteric communication from the
ligand binding site to the G-protein coupling site plays a role in G-protein selectivity very little is known
about the mechanism of this communication and the residues involved in this process. Here we
propose to (1) use the computational method Allosteer developed in our lab in combination with FRET
sensors, NanoBRET assays and cell based downstream assays to delineate the allosteric network of
GPCR residues involved in regulating G-protein selectivity in 9 different Gs, Gi and Gq coupled class A
GPCRs in cellular conditions. The second aim is to understand the effect of partial agonists in
comparison to the full agonists, on the GPCR-G-protein selective coupling. We will identify the hotspot
residues on the G-protein and GPCRs when bound to partial agonists and compare the similarities and
differences with full agonists. The outcome of the proposed work will provide the role of allosteric
network of residues in G-protein selectivity and how partial agonists modulate the receptor
conformations. This will push forward our understanding of the biological process of how GPCRs
recognize their cognate G-proteins in live cells.

## Key facts

- **NIH application ID:** 10762995
- **Project number:** 5R01GM117923-08
- **Recipient organization:** BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
- **Principal Investigator:** Nagarajan Vaidehi
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $352,000
- **Award type:** 5
- **Project period:** 2017-05-17 → 2026-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10762995

## Citation

> US National Institutes of Health, RePORTER application 10762995, Structural dynamics underlying GPCR-G protein selectivity (5R01GM117923-08). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10762995. Licensed CC0.

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