# G Protein Coupled Receptor Structure, Dynamics and Signaling

> **NIH NIH R01** · STANFORD UNIVERSITY · 2021 · $544,920

## Abstract

Project Summary
G protein coupled receptors (GPCRs) are the largest family of receptors for hormones and neurotransmitters
and therefore the largest group of targets for new therapeutics for a very broad spectrum of diseases including
neuropsychiatric, cardiovascular, pulmonary and metabolic disorders, cancer and AIDS. While initially thought
to signal exclusively though 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 crystallography and several biophysical methods to
characterize the structure and dynamic character of the β2 adrenergic receptor (β2AR). These studies provide
evidence that the β2AR is 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:** 10244897
- **Project number:** 5R01NS028471-31
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Brian K Kobilka
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $544,920
- **Award type:** 5
- **Project period:** 1990-04-01 → 2023-08-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10244897

## Citation

> US National Institutes of Health, RePORTER application 10244897, G Protein Coupled Receptor Structure, Dynamics and Signaling (5R01NS028471-31). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10244897. Licensed CC0.

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