# Structural Basis of G-protein selectivity in GPCRs using Multiscale Dynamics

> **NIH NIH R01** · BECKMAN RESEARCH INSTITUTE/CITY OF HOPE · 2020 · $551,908

## Abstract

Summary:
Title: Structural Basis of G-protein selectivity in GPCRs using Multiscale Dynamics
Upon binding to agonists G protein-coupled receptors (GPCRs) mediate multiple signaling pathways by
coupling to intracellular transducer proteins such as G proteins and/or β-arrestins. Certain agonists
exhibit selectivity in their efficacy to specific G-protein signaling pathways. Such selective ligands
provide precise therapeutic benefits with fewer side effects as drugs compared to GPCR-targeted drugs
in the market. There are very few G-protein selective GPCR agonists known to date, because
designing G-protein selective agonists is a daunting experimental challenge. Additionally, there is a
serious lack of understanding of structural information on how GPCRs modulate their functional
selectivity for their cognate G-protein in cells. There are several contributing factors to how an agonist-
GPCR pair shows selectivity to specific G-protein. These factors include, nature of conformational
ensembles of the agonist-GPCR-G-protein complexes, and several cellular factors. Delineating the
contribution from the structural ensemble of the agonist-GPCR-G-protein complexes has been sparse
due to huge experimental challenges in crystallography and NMR of these complexes. We propose to
combine two state-of-the-art dynamics techniques, such as ensemble based multi-resolution molecular
dynamics method tightly integrated in an iterative fashion with scalable genetically coded FRET sensor
biophysical measurements in live cells, to probe the structural basis of G-protein selectivity. The
scalability of these two techniques is a huge advantage to probe the functional selectivity of several
agonist-GPCR pairings. We propose to use the combination of these two techniques to (a) identify the
structural determinants in the agonist-GPCR complex that contribute significantly to G-protein
selectivity in nine different agonist-GPCR pairs. (b) We also propose to delineate the structural
determinants that contribute to functional selectivity when the GPCR is bound to a partial agonist as
opposed to a full agonist, and when the agonist-GPCR is also bound to an allosteric modulator. The
outcome of the proposed work will enable structure based design of selective agonists for class A
GPCRs, and also provide an understanding of the biological process of how GPCRs recognize their
cognate G-proteins in live cells.

## Key facts

- **NIH application ID:** 9850264
- **Project number:** 5R01GM117923-04
- **Recipient organization:** BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
- **Principal Investigator:** Sivaraj Sivaramakrishnan
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $551,908
- **Award type:** 5
- **Project period:** 2017-05-17 → 2021-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9850264

## Citation

> US National Institutes of Health, RePORTER application 9850264, Structural Basis of G-protein selectivity in GPCRs using Multiscale Dynamics (5R01GM117923-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9850264. Licensed CC0.

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