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TitleMechanism and function of GPR3 regulated by a negative allosteric modulator.
Journal, issue, pagesNat Commun, Vol. 16, Issue 1, Page 7988, Year 2025
Publish dateAug 27, 2025
AuthorsGeng Chen / Jana Bláhová / Nico Staffen / Harald Hübner / Nadja Nunhöfer / Chen Qiu / Peter Gmeiner / Dorothee Weikert / Yang Du / Jun Xu /
PubMed AbstractAllosteric 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 ...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.
External linksNat Commun / PubMed:40866348 / PubMed Central
MethodsEM (single particle)
Resolution3.1 - 3.83 Å
Structure data

63702

9m88

EMDB-63702, PDB-9m88:
PGS fused GPR3 dimer with antagonist AF64394
Method: EM (single particle) / Resolution: 3.1 Å

63717

9m8p

EMDB-63717, PDB-9m8p:
GPR3 dimer with antagonist AF64394
Method: EM (single particle) / Resolution: 3.42 Å

63723

9m8v

EMDB-63723, PDB-9m8v:
dimer-GPR3-Gs complex
Method: EM (single particle) / Resolution: 3.83 Å

Chemicals

ChemComp-5YM:
(Z)-N-(2-hydroxyethyl)octadec-9-enamide / agonist*YM

PDB-1em1:
X-RAY CRYSTAL STRUCTURE FOR HUMAN MANGANESE SUPEROXIDE DISMUTASE, Q143A

ChemComp-1DO:
1-DODECANOL


PDB Unreleased entry

PDB-1em3: CRYSTAL STRUCTURE OF LUFFACULIN, A RIBOSOME-INACTIVATING PROTEIN AT 2.0A RESOLUTION

PDB-1eq8:
THREE-DIMENSIONAL STRUCTURE OF THE PENTAMERIC HELICAL BUNDLE OF THE ACETYLCHOLINE RECEPTOR M2 TRANSMEMBRANE SEGMENT

PDB-1em2:
Star-related lipid transport domain of MLN64

PDB-1ajd:
THREE-DIMENSIONAL STRUCTURE OF THE D153G MUTANT OF E. COLI ALKALINE PHOSPHATASE: A MUTANT WITH WEAKER MAGNESIUM BINDING AND INCREASED CATALYTIC ACTIVITY

ChemComp-HOH:
WATER

Source
  • homo sapiens (human)
  • pyrococcus abyssi (archaea)
  • escherichia coli (E. coli)
KeywordsMEMBRANE PROTEIN / GPCR / dimer / antagonist / G-protein complex

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