# Structural and Functional Studies of Rhodopsin and G-Protein Coupled Receptor Kinases

> **NIH NIH R01** · VAN ANDEL RESEARCH INSTITUTE · 2020 · $365,750

## Abstract

PROJECT SUMMARY/ABSTRACT
Humans have more than 800 different G protein-coupled receptors (GPCRs), which form the
largest family of cell-surface receptors and account for ~30% of all therapeutic drug targets.
Upon activation by agonists, GPCRs adopt distinct activated states that allow them to couple
either to G proteins, to initiate G protein-mediated signaling, or to GPCR kinases (GRKs), which
phosphorylate GPCRs to enable their interactions with arrestins to terminate G protein
activation and initiate arrestin-mediated signaling. While physiological agonists initiate both G
protein- and arrestin-mediated signaling, often only one of the two pathways is therapeutically
beneficial, while the other pathway is responsible for unwanted side effects. Given the
importance of GPCRs as drug targets, there is huge interest in developing “biased” GPCR
agonist that signal predominantly through only one of the two pathways. However, the critical
barrier for rationally developing biased agonist is the limited information on how GRKs interact
with GPCRs and the complete absence of any high resolution GPCR/GRK structure. Crystal
and cryo-EM structures of four GPCRs in complex with G proteins and of one GPCR in complex
with an arrestin have provided an emerging understanding of the receptor conformations
required for G protein and arrestin coupling, yet a mechanistic understanding of how GRKs bind
and phosphorylate GPCRs have remained elusive due to the highly transient nature of this
interaction. The objective of this proposal is to bridge this critical gap in knowledge by
exploiting the interaction between rhodopsin and GRK1 as a paradigm to determine the
mechanistic and structural basis of the targetable interaction between GPCRS and GRKs.
SIGNIFICANCE: Completion of the proposed aims will reveal the first mechanistic basis of
GRK/GPCR recognition and reveal the GPCR/GRK conformation that enables GRK binding and
receptor phosphorylation. This information is of paramount importance for the rational design of
therapeutic biased agonists for the treatment of a broad spectrum of diseases.

## Key facts

- **NIH application ID:** 10012941
- **Project number:** 5R01GM127710-03
- **Recipient organization:** VAN ANDEL RESEARCH INSTITUTE
- **Principal Investigator:** Karsten Melcher
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $365,750
- **Award type:** 5
- **Project period:** 2018-04-01 → 2021-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10012941

## Citation

> US National Institutes of Health, RePORTER application 10012941, Structural and Functional Studies of Rhodopsin and G-Protein Coupled Receptor Kinases (5R01GM127710-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10012941. Licensed CC0.

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