# Molecular Mechanisms of G protein-coupled Receptor Biased Signaling

> **NIH NIH R35** · MEDICAL COLLEGE OF WISCONSIN · 2024 · $421,200

## Abstract

Project Summary
G protein-coupled receptors (GPCRs) are an important superfamily of seven transmembrane proteins involved
in cell-to-cell communication essential for sensing, movement, and thought processes. A significant portion of
current approved drug therapies target GPCRs, but suffer from “on-target” side-effects related to the
engagement of differential signaling pathways known as “functional selectivity” or “biased signaling.” Exploiting
biased signaling represents a promising approach toward designing pathway-selective drugs with better “on-
target” profiles, but the mechanisms at the structural level that lead to biased signaling are still poorly
understood. Recent advances in structural details of biased ligand recognition have led to the identification of
common binding pocket motifs important for `switching' balanced agonists toward biased agonists, and vice
versa. Using a structure-based and chemical biology approach, my laboratory aims to use a variety of recently
discovered biased ligands to uncover common mechanisms within the binding pocket that govern biased
signaling at key GPCR targets. Strategies will incorporate a combination of structure-guided mutagenesis, use
of structure-activity relationships (SAR) for recently discovered biased ligands, and high-throughput assays
measuring ligand kinetics, G protein dissociation, second messenger production, β-arrestin recruitment, and
internalization. This approach focuses on molecular determinants between G protein and β-arrestin-bias
agonism at key receptors that have historically shown biased agonist phenomena. Through these studies, a
comprehensive mechanistic understanding into GPCR biased signaling will guide researchers toward
generations of superior therapeutics.
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## Key facts

- **NIH application ID:** 10842093
- **Project number:** 2R35GM133421-06
- **Recipient organization:** MEDICAL COLLEGE OF WISCONSIN
- **Principal Investigator:** John D McCorvy
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $421,200
- **Award type:** 2
- **Project period:** 2019-08-01 → 2029-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10842093

## Citation

> US National Institutes of Health, RePORTER application 10842093, Molecular Mechanisms of G protein-coupled Receptor Biased Signaling (2R35GM133421-06). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10842093. Licensed CC0.

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