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TitleStructural basis of oligomerization-modulated activation and autoinhibition of orphan receptor GPR3.
Journal, issue, pagesCell Rep, Vol. 44, Issue 4, Page 115478, Year 2025
Publish dateMar 28, 2025
AuthorsHao Chang / Xiaoting Li / Hongqing Tu / Lijie Wu / Yanan Yu / Junlin Liu / Na Chen / Wei L Shen / Tian Hua /
PubMed AbstractG protein-coupled receptor 3 (GPR3) is a class A orphan receptor characterized by high constitutive activity in the G signaling pathway. GPR3 has been implicated in Alzheimer's disease and the ...G protein-coupled receptor 3 (GPR3) is a class A orphan receptor characterized by high constitutive activity in the G signaling pathway. GPR3 has been implicated in Alzheimer's disease and the regulation of thermogenesis in human adipocytes, yet the molecular mechanisms underlying its self-activation and potential endogenous modulators remain unclear. In this study, we present cryo-electron microscopy (cryo-EM) structures of GPR3 in different oligomerization states, both in the absence and presence of G protein. Notably, in addition to the monomeric form of GPR3, our findings reveal a functional GPR3 dimer with an extensive dimer interface-a feature rarely observed in class A GPCRs. Moreover, oligomerization appears to be linked to a unique autoinhibition mechanism involving intracellular loops, which may regulate GPR3 signaling. Collectively, these results provide new insights into the oligomerization-modulated activation of orphan GPCRs, advancing our understanding of their signaling properties.
External linksCell Rep / PubMed:40158220
MethodsEM (single particle)
Resolution3.06 - 3.66 Å
Structure data

EMDB-63522, PDB-9lyd:
Cryo-EM structure of GPR3-1IU9 complex
Method: EM (single particle) / Resolution: 3.66 Å

EMDB-63523, PDB-9lyc:
Cryo-EM structure of GPR3-G protein-dimer complex
Method: EM (single particle) / Resolution: 3.06 Å

EMDB-63525, PDB-9lyb:
Cryo-EM structure of GPR3-G protein-monomer complex
Method: EM (single particle) / Resolution: 3.16 Å

Source
  • homo sapiens (human)
KeywordsSTRUCTURAL PROTEIN / GPCR / G protein / cryo-EM / membrane protein

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