9XQC
A composite Cryo-EM structure of GPR75
Summary for 9XQC
| Entry DOI | 10.2210/pdb9xqc/pdb |
| EMDB information | 67110 |
| Descriptor | G subunit alpha (q), Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1, Antibody fragment scFv16, ... (6 entities in total) |
| Functional Keywords | gpcr, gpr75, membrane protein/immune system, membrane protein-immune system complex |
| Biological source | Homo sapiens More |
| Total number of polymer chains | 5 |
| Total formula weight | 161896.71 |
| Authors | |
| 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 Cited by 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: 41545757DOI: 10.1038/s41401-025-01720-6 PDB entries with the same primary citation |
| Experimental method | ELECTRON MICROSCOPY (3 Å) |
Structure validation
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