# G protein coupled receptor structure, dynamics, and signaling.

> **NIH NIH R35** · STANFORD UNIVERSITY · 2024 · $627,837

## Abstract

Project Summary
G protein coupled receptors (GPCRs) are the largest family of receptors for neurotransmitters and hormones,
and are therefore the largest group of targets for new therapeutics for a very broad spectrum of diseases
including neurologic, cardiovascular, pulmonary and metabolic disorders. While initially thought to signal
exclusively through G proteins and function as two-state switches activated by hormones and neurotransmitters,
research over the past 30 years has revealed that most GPCRs have complex and diverse signaling behaviors.
A single GPCR can activate more than one G protein subtype as well as G protein independent signaling
pathways such as arrestins. Many GPCRs exhibit basal, agonist-independent activity. When considering one of
the several possible downstream signaling pathways, a drug acting at the orthosteric binding pocket may exhibit
one of four efficacy profiles. It may behave as an inverse agonist, suppressing basal activity, a full agonist,
maximally activating the pathway, a partial agonist, promoting submaximal activity even at saturating
concentrations, or a neutral antagonist, having no effect on basal signaling, but blocking the binding of other
orthosteric ligands. The efficacy profile of a given ligand may differ for different signaling pathways such that a
drug may behave as an agonist for a specific G protein subtype or arrestin while have no effect or inhibiting other
signaling pathways. This pathway selective (or biased) signaling has become an important consideration for drug
discovery, since one signaling pathway may produce therapeutic effects while another may lead to adverse
effects.
During the previous funding period we have applied cryo-electron microscopy and several biophysical methods
to characterize the structure and dynamic character of several Family A GPCRs, as well as a Family B and
Family C GPCR. These studies provide evidence that these GPCRs are highly dynamic and conformationally
complex. We hypothesize that this complexity is essential for their functional versatility, and believe that a more
detailed understanding of this complex conformational landscape will provide mechanistic insights into targeted
activation of a specific pathway with biased ligands. The goal of this proposal will be to understand the structural
basis for GPCR signaling through multiple pathways using methods that will provide high-resolution structural
constraints and characterize protein dynamics under more physiologic conditions.

## Key facts

- **NIH application ID:** 10888044
- **Project number:** 1R35NS137408-01
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Brian K Kobilka
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $627,837
- **Award type:** 1
- **Project period:** 2024-05-15 → 2032-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10888044

## Citation

> US National Institutes of Health, RePORTER application 10888044, G protein coupled receptor structure, dynamics, and signaling. (1R35NS137408-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10888044. Licensed CC0.

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