# Structural Basis and Molecular Mechanism of GPCR-Arrestin Interactions

> **NIH NIH R35** · INDIANA UNIVERSITY INDIANAPOLIS · 2024 · $396,250

## Abstract

Project Summary/Abstract
 G protein coupled receptors are essentially the molecular messengers of the cell,
transducing signals from outside to inside. The signals are remarkably diverse, including a single
photon, ion like calcium, neurotransmitters and hormones. Humans have more than 800 GPCRs
for recognizing different signals, but only three types of transducers, G proteins, GPCR kinases
(GRKs) and arrestins. GRKs phosphorylate GPCRs whereas G proteins and arrestins directly
bind GPCRs, send the signal to downstream effectors and cause a cellular response. Comparing
structures of GPCR bound to G protein and arrestin will provide valuable insights into the
functional selectivity and guide the design of more potent drugs with better safety profiles. There
are currently >300 structures of GPCR−G protein complex reported but only 8 published
structures of GPCR−arrestin complex, which highlights the relative difficulty in obtaining suitable
arrestin complexes for structural analysis. My lab focuses on the understudied GPCR−arrestin
signaling pathway. We have developed a novel tool which stabilizes GPCR−arrestin complexes
for cryo-electron microscopy studies and used that to visualize how the atypical chemokine
receptor 3 engages arrestins in various ways at near-atomic resolution. For the next five years,
we plan to expand the study to many important GPCR−arrestin pairs to understand the structural
details to aid the design of selective interventions. This study will open the way to a detailed
dissection of the mechanism of arrestin-mediated GPCR signaling but also to structure-based
drug design.

## Key facts

- **NIH application ID:** 10892255
- **Project number:** 5R35GM151033-02
- **Recipient organization:** INDIANA UNIVERSITY INDIANAPOLIS
- **Principal Investigator:** Qiuyan Chen
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $396,250
- **Award type:** 5
- **Project period:** 2023-08-01 → 2028-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10892255

## Citation

> US National Institutes of Health, RePORTER application 10892255, Structural Basis and Molecular Mechanism of GPCR-Arrestin Interactions (5R35GM151033-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10892255. Licensed CC0.

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