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Updated: Aug 12, 2025
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A Kinetic Fluorescence-based Ca2+ Mobilization Assay to Identify G Protein-coupled Receptor Agonists, Antagonists, and Allosteric Modulators
Published on: February 20, 2018
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Asymmetric activation of class C GPCRs
Hongnan Liu1, Yanjun Li1, Yang Gao2
1Department of Cardiology of Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China; Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, China.
Progress in Molecular Biology and Translational Science
|January 27, 2023
Summary
Class C G-protein-coupled receptors (GPCRs) activate asymmetrically, utilizing a unique TM6-TM6 interface for Gi protein coupling. This mechanism differs from other GPCRs and informs therapeutic design.
Area of Science:
- Biochemistry
- Structural Biology
- Pharmacology
Background:
- Class C G-protein-coupled receptors (GPCRs) are dimeric proteins with large extracellular domains.
- Recent cryo-electron microscopy (cryo-EM) structures reveal asymmetric activation mechanisms in GABAB, CaSR, and mGlu receptors.
Approach:
- This review discusses the structural rearrangements and molecular interactions underlying asymmetric activation in class C GPCRs.
- Focuses on the unique seven-transmembrane domain (7TM) interface and Gi protein coupling.
Key Points:
- Class C GPCRs activate asymmetrically, with G-protein coupling occurring on one protomer.
- A conserved asymmetric TM6-TM6 interface forms upon activation, distinct from class A and B GPCRs.
- Allosteric modulators bind in distinct conformations to regulate receptor activity.
Conclusions:
- Class C GPCRs employ a novel mechanism for G protein activation via asymmetric signaling.
- Understanding these mechanisms provides insights for developing targeted therapeutics for class C GPCRs.
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