# Discovering the mechanism of GPCR-mediated arrestin stimulation to enable effective drug therapies

> **NIH NIH R01** · STANFORD UNIVERSITY · 2020 · $309,440

## Abstract

Project Summary
Medicines that cause G protein–coupled receptors (GPCRs) to selectively stimulate arrestins, or
to selectively avoid stimulation of arrestins, promise more effective and safer treatments for a
wide variety of diseases, including neuropsychiatric, cardiovascular, pulmonary and metabolic
disorders. Despite intense study of GPCR–arrestin interactions in both academia and the
pharmaceutical industry, and despite dramatic recent advances in the structural biology of
GPCRs and arrestins, the mechanism by which GPCRs stimulate arrestins remains poorly
understood. Likewise, the means by which GPCRs might achieve selectivity for or against
arrestin signaling remains unclear. The proposed research will utilize atomic-level molecular
dynamics simulations to address these challenges, thereby providing a foundation for the
design of functionally selective GPCR-targeted drugs with desired effects on arrestins.
Aim 1 is to determine the activation mechanism of arrestin, pinpointing which of the GPCR–
arrestin interaction surfaces drives arrestin activation and discovering the allosteric coupling
between regions of arrestin that causes these structural changes to take place. The remaining
aims are to determine the effect of both GPCR conformation (Aim 2) and GPCR
phosphorylation pattern (Aim 3) on arrestin binding and activation. This will reveal how a GPCR
can favor or disfavor arrestin recruitment and signaling relative to G protein recruitment and
signaling. It will also reveal how a GPCR can favor specific arrestin conformations, potentially
stimulating some of arrestin’s downstream effects without stimulating others.
The proposed research will rely on state-of-the-art simulation methods that have recently
enabled the determination of functional mechanisms of GPCRs, G proteins, transporters, and
other proteins. It will also benefit from close collaborations with multiple experimentalists: results
from crystallography, fluorescence spectroscopy, NMR, electron paramagnetic resonance, and
cell signaling experiments will combine to both guide and validate the simulations. This proposal
is significant not only because it will illuminate a quintessential biological signaling process but
also because it will reveal a key part of the structural basis for functional selectivity at GPCRs. It
will thus provide a foundation for the rational design of safer and more effective medications
acting at GPCRs, which are by far the largest class of drug targets.

## Key facts

- **NIH application ID:** 9843679
- **Project number:** 5R01GM127359-03
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Ron Dror
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $309,440
- **Award type:** 5
- **Project period:** 2018-04-01 → 2023-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9843679

## Citation

> US National Institutes of Health, RePORTER application 9843679, Discovering the mechanism of GPCR-mediated arrestin stimulation to enable effective drug therapies (5R01GM127359-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9843679. Licensed CC0.

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