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TitleCryo-EM structures of GPR75 reveal an occluded orthosteric pocket challenging conventional drug discovery paradigms for an anti-obesity target.
Journal, issue, pagesActa Pharmacol Sin, Year 2026
Publish dateJan 16, 2026
AuthorsZi-Ning Zhu / Chong-Zhao You / Qing-Ning Yuan / Jiu-Yin Xu / Zong-Yue Gu / Zheng Huang / Miao Liu / Bei Shan / James Jiqi Wang / Wen Hu / Kai Wang / Wan-Chao Yin / You-Wei Xu / H Eric Xu / Can-Rong Wu /
PubMed AbstractThe global obesity epidemic, affecting over 650 million adults, demands innovative therapeutics. GPR75 has emerged as a promising anti-obesity target, with genetic evidence linking loss-of-function ...The global obesity epidemic, affecting over 650 million adults, demands innovative therapeutics. GPR75 has emerged as a promising anti-obesity target, with genetic evidence linking loss-of-function variants to protection against obesity and type 2 diabetes. However, structural insights have remained elusive due to GPR75's inherent expression and stabilization challenges. Here we present the cryo-EM structures of human GPR75 in apo and Gq-coupled states, achieved through advanced stabilization techniques including NanoBiT and molecular glue approaches. Our structures reveal unique architectural features: a completely collapsed extracellular domain eliminates the traditional orthosteric binding pocket, raising critical questions about previously reported small molecule ligands. GPR75 assumes active-like conformation in both apo and G protein complexed structures through unique molecular switches-the canonical DRY motif is replaced by HRL, abolishing the ionic lock, while a distinctive Lys134-Asp210 salt bridge stabilizes the active conformation without ligand binding. This dramatic structural divergence from conventional GPCRs necessitates alternative therapeutic strategies targeting allosteric sites or protein-protein interactions rather than orthosteric pockets. Our findings establish a crucial structural framework for developing next-generation anti-obesity therapeutics.
External linksActa Pharmacol Sin / PubMed:41545757
MethodsEM (single particle)
Resolution2.87 - 3.91 Å
Structure data

EMDB-67108: Cryo-EM structure of Receptor of GPR75
Method: EM (single particle) / Resolution: 3.5 Å

EMDB-67109: The cryo_EM structure of GPR75 complex
Method: EM (single particle) / Resolution: 2.87 Å

67110

9xqc

EMDB-67110, PDB-9xqc:
A composite Cryo-EM structure of GPR75
Method: EM (single particle) / Resolution: 3.0 Å

67119

9xqn

EMDB-67119, PDB-9xqn:
Cryo-EM structure of apo form of GPR75-bRIL-Fab complex
Method: EM (single particle) / Resolution: 3.91 Å

Chemicals

ChemComp-HOH:
WATER

Source
  • homo sapiens (human)
  • mus musculus (house mouse)
  • escherichia coli k-12 (bacteria)
  • escherichia coli (E. coli)
KeywordsMEMBRANE PROTEIN/IMMUNE SYSTEM / GPCR / GPR75 / MEMBRANE PROTEIN-IMMUNE SYSTEM complex

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