Mechanism and function of GPR3 regulated by a negative allosteric modulator

Chen G, Bláhová J, Staffen N, Hübner H, Nunhöfer N, Qiu C, Gmeiner P, Weikert D, Du Y, Xu J (2025)

Publication Language: English

Publication Type: Journal article

Publication year: 2025

Journal

Nature Communications Nature Publishing Group: Nature Communications

Book Volume: 16

Article Number: 7988

Journal Issue: 1

DOI: 10.1038/s41467-025-63422-1

Abstract

Allosteric modulators have gained substantial interest in current GPCR drug discovery. Here, we present a mechanism of allosteric modulation involving the dimerization of GPR3, a promising drug target for metabolic diseases and central nervous system disorders. We show that GPR3 forms constitutive homodimers in live cells and reveal that the inhibitor AF64394 functions as a negative allosteric modulator (NAM) specifically targeting dimeric GPR3. Using cryogenic electron microscopy (cryo-EM), we determine the structures of the AF64394-bound GPR3 dimer and its dimer-Gs signaling complex. These high-resolution structures reveal that AF64394 binds to the transmembrane dimer interface. AF64394 binding prevents the dissociation of the GPR3 dimer upon engagement with Gs and restrains transmembrane helix 5 in an inactive-like intermediate conformation, leading to reduced coupling with Gs. Our studies unveil a mechanism of dimer-specific inhibition of signaling with significant implications for the discovery of drugs targeting GPCRs capable of dimerization.

Authors with CRIS profile

Jana Bláhová Lehrstuhl für Pharmazeutische Chemie Nico Staffen Lehrstuhl für Pharmazeutische Chemie Harald Hübner Lehrstuhl für Pharmazeutische Chemie Peter Gmeiner Lehrstuhl für Pharmazeutische Chemie Dorothée Weikert Lehrstuhl für Pharmazeutische Chemie

Involved external institutions

Sun Yat-Sen University CN China (CN) The Chinese University of Hong Kong (CUHK) CN China (CN) Southern University of Science and Technology CN China (CN)

How to cite

APA:

Chen, G., Bláhová, J., Staffen, N., Hübner, H., Nunhöfer, N., Qiu, C.,... Xu, J. (2025). Mechanism and function of GPR3 regulated by a negative allosteric modulator. Nature Communications, 16(1). https://doi.org/10.1038/s41467-025-63422-1

MLA:

Chen, Geng, et al. "Mechanism and function of GPR3 regulated by a negative allosteric modulator." Nature Communications 16.1 (2025).

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