9M88

PGS fused GPR3 dimer with antagonist AF64394

This is a non-PDB format compatible entry.

Summary for 9M88

• Entry DOI: 10.2210/pdb9m88/pdb
• EMDB information: 63702
• Descriptor: GPR3, Glycogen synthase, (Z)-N-(2-hydroxyethyl)octadec-9-enamide, ... (8 entities in total)
• Functional Keywords: gpcr, dimer, antagonist, membrane protein
• Biological source: Homo sapiens; More
• Total number of polymer chains: 4
• Total formula weight: 190245.78

Authors

Geng, C.,Jun, X. (deposition date: 2025-03-11, release date: 2025-09-24, Last modification date: 2025-10-01)

Primary citation

Chen, G.,Blahova, J.,Staffen, N.,Hubner, H.,Nunhofer, N.,Qiu, C.,Gmeiner, P.,Weikert, D.,Du, Y.,Xu, J.
Mechanism and function of GPR3 regulated by a negative allosteric modulator.
Nat Commun, 16:7988-7988, 2025

PubMed 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.

PubMed: 40866348
DOI: 10.1038/s41467-025-63422-1

Experimental method

ELECTRON MICROSCOPY (3.1 Å)