# Molecular Mechanisms of G protein-coupled Receptor Biased Signaling

> **NIH NIH R35** · MEDICAL COLLEGE OF WISCONSIN · 2021 · $385,000

## Abstract

Research 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 advancement in structural knowledge of biased ligand recognition has led to the
identification of binding pocket motifs, such as extracellular loop 2 (EL2) and transmembrane (TM) 7, important
for `switching' biased signaling via direct ligand engagement. Using a structure-based approach, my laboratory
aims to use a variety of chemical biology and biophysical approaches to uncover common mechanisms within
the binding pocket that govern biased signaling. Strategies will incorporate a combination of structure-guided
mutagenesis, orthosteric/allosteric biased ligands, kinetic monitoring of G protein function and β-arrestin
recruitment using luciferase and bioluminescent resonance energy transfer (BRET) techniques, and structure-
`functional selectivity' relationships (SFSRs) to ultimately to pin-point key GPCR binding motifs involved in
effector switching. This approach focuses on key receptors where there is structural knowledge and G protein
and β-arrestin-biased ligands available. Through these studies, a comprehensive mechanistic understanding
into GPCR biased signaling will guide researchers toward a new generation of superior therapeutics.
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## Key facts

- **NIH application ID:** 10164807
- **Project number:** 5R35GM133421-03
- **Recipient organization:** MEDICAL COLLEGE OF WISCONSIN
- **Principal Investigator:** John D McCorvy
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $385,000
- **Award type:** 5
- **Project period:** 2019-08-01 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10164807

## Citation

> US National Institutes of Health, RePORTER application 10164807, Molecular Mechanisms of G protein-coupled Receptor Biased Signaling (5R35GM133421-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10164807. Licensed CC0.

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