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Mechanism and function of GPR3 regulated by a negative allosteric modulator
Geng Chen1,2,3, Jana Bláhová4, Nico Staffen4
1School of Medicine, Shenzhen Campus of Sun Yat-sen University, Sun Yat-sen University, Shenzhen, China.
Nature Communications
|August 27, 2025
Summary
Researchers discovered a new way drugs can block G protein-coupled receptors (GPCRs). A drug called AF64394 targets GPR3 dimers, preventing them from signaling and offering new avenues for metabolic and CNS disorder treatments.
Area of Science:
- Biochemistry
- Structural Biology
- Pharmacology
Background:
- G protein-coupled receptors (GPCRs) are key drug targets.
- Allosteric modulators offer precise control over GPCR activity.
- GPR3 is implicated in metabolic and CNS disorders.
Purpose of the Study:
- To elucidate the mechanism of allosteric modulation of GPR3.
- To investigate the role of GPR3 dimerization in its function.
- To determine the structural basis for inhibition by AF64394.
Main Methods:
- Cellular assays to study GPR3 dimerization and signaling.
- Cryogenic electron microscopy (cryo-EM) for structural determination.
- Biochemical assays to analyze G protein coupling.
Main Results:
- GPR3 forms constitutive homodimers in live cells.
- AF64394 acts as a negative allosteric modulator (NAM) targeting dimeric GPR3.
- Cryo-EM structures reveal AF64394 binding at the dimer interface, stabilizing an inactive conformation and reducing Gs coupling.
Conclusions:
- AF64394 inhibits GPR3 signaling through a dimer-specific mechanism.
- This study reveals a novel allosteric inhibition strategy targeting GPCR dimers.
- Findings have significant implications for developing drugs for metabolic and CNS disorders targeting dimeric GPCRs.
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