2. Academic Validation
  3. Structural basis of oligomerization-modulated activation and autoinhibition of orphan receptor GPR3

Structural basis of oligomerization-modulated activation and autoinhibition of orphan receptor GPR3

  • Cell Rep. 2025 Apr 22;44(4):115478. doi: 10.1016/j.celrep.2025.115478.
Hao Chang 1,  Xiaoting Li 2,  Hongqing Tu 3,  Lijie Wu 2,  Yanan Yu 1,  Junlin Liu 2,  Na Chen 2,  Wei L Shen 4,  Tian Hua 5
Affiliations

Affiliations

  • 1 iHuman Institute, ShanghaiTech University, Shanghai 201210, China; School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China.
  • 2 iHuman Institute, ShanghaiTech University, Shanghai 201210, China.
  • 3 School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China.
  • 4 School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China. Electronic address: shenwei@shanghaitech.edu.cn.
  • 5 iHuman Institute, ShanghaiTech University, Shanghai 201210, China; School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China. Electronic address: huatian@shanghaitech.edu.cn.
PMID: 40158220 DOI: 10.1016/j.celrep.2025.115478
Abstract

G protein-coupled receptor 3 (GPR3) is a class A Orphan Receptor characterized by high constitutive activity in the Gs 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.

Keywords

CP: Cell biology; CP: Molecular biology; GPCR; GPR3; autoinhibition; dimerization; structural biology.

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