9XQN

Cryo-EM structure of apo form of GPR75-bRIL-Fab complex

Summary for 9XQN

• Entry DOI: 10.2210/pdb9xqn/pdb
• EMDB information: 67119
• Descriptor: Probable G-protein coupled receptor 75,Soluble cytochrome b562, Fab24 H, Fab24 L (3 entities in total)
• Functional Keywords: gpcr, gpr75, membrane protein/immune system, membrane protein-immune system complex
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 3
• Total formula weight: 71256.61

Authors

Wu, C.,Yuan, Q. (deposition date: 2025-11-18, release date: 2026-02-04)

Primary citation

Zhu, Z.N.,You, C.Z.,Yuan, Q.N.,Xu, J.Y.,Gu, Z.Y.,Huang, Z.,Liu, M.,Shan, B.,Wang, J.J.,Hu, W.,Wang, K.,Yin, W.C.,Xu, Y.W.,Xu, H.E.,Wu, C.R.
Cryo-EM structures of GPR75 reveal an occluded orthosteric pocket challenging conventional drug discovery paradigms for an anti-obesity target.
Acta Pharmacol.Sin., 2026

PubMed Abstract: 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.

PubMed: 41545757
DOI: 10.1038/s41401-025-01720-6

Experimental method

ELECTRON MICROSCOPY (3.91 Å)