@article{APS11524,
author = {Zi-ning Zhu and Chong-zhao You and Qing-ning Yuan and Jiu-yin Xu and Zong-yue Gu and Zheng Huang and Miao Liu and Bei Shan and James Jiqi Wang and Wen Hu and Kai Wang and Wan-chao Yin and You-wei Xu and H. Eric Xu and Can-rong Wu},
title = {Cryo-EM structures of GPR75 reveal an occluded orthosteric pocket challenging conventional drug discovery paradigms for an anti-obesity target},
journal = {Acta Pharmacologica Sinica},
volume = {14},
number = {5},
year = {2026},
keywords = {},
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.},
issn = {1745-7254}, url = {http://www.chinaphar.com/article/view/11524}
}