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Cryo-EM structures of GPR75 reveal an occluded orthosteric pocket challenging conventional drug discovery paradigms for an anti-obesity target

文献类型：期刊论文

作者Zhu, Zi-ning1,8; You, Chong-zhao7; Yuan, Qing-ning1,6; Xu, Jiu-yin6; Gu, Zong-yue1; Huang, Zheng5; Liu, Miao5; Shan, Bei5; Wang, James Jiqi3,4; Hu, Wen8
刊名ACTA PHARMACOLOGICA SINICA
出版日期2026-01-16
页码10
ISSN号1671-4083
DOI10.1038/s41401-025-01720-6
英文摘要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.
WOS关键词OBESITY
资助项目Chinese Academy of Sciences ; National Key R&D Program of China[2022YFA1302900] ; National Key R&D Program of China[2022YFC2703105] ; National Natural Science Foundation of China[32301016] ; National Natural Science Foundation of China[32130022] ; National Natural Science Foundation of China[82495184] ; National Natural Science Foundation of China[82121005] ; National Natural Science Foundation of China[82404881] ; National Key R&D Program Strategic Scientific and Technological Innovation Cooperation Key Project[2022YFE0203600] ; Ministry of Science and Technology ; CAS Strategic Priority Research Program[XDB37030103] ; Shanghai Municipal Science and Technology Major Project ; Strategic Priority Research Program of the Chinese Academy of Sciences[XDB0830000]
WOS研究方向Chemistry ; Pharmacology & Pharmacy
语种英语
WOS记录号WOS:001662281400001
出版者NATURE PUBL GROUP
源URL[http://119.78.100.183/handle/2S10ELR8/322640]  
专题国家级研究中心_原创新药研究全国重点实验室
通讯作者Xu, H. Eric; Wu, Can-rong
作者单位1.Nanjing Univ Chinese Med, Nanjing 210023, Peoples R China
2.Chinese Acad Sci, Zhongshan Inst Drug Discovery, Shanghai Inst Mat Med, Zhongshan 528400, Peoples R China
3.Huazhong Univ Sci & Technol, Tongji Hosp, Tongji Med Coll, Hubei Key Lab Genet & Mol Mech Cardiol Disorders, Wuhan 430000, Peoples R China
4.Huazhong Univ Sci & Technol, Tongji Hosp, Tongji Med Coll, Div Cardiol,Dept Internal Med, Wuhan 430000, Peoples R China
5.BioFront Therapeut, Beijing 100089, Peoples R China
6.Shanghai Jiao Tong Univ, Natl Res Ctr Translat Med Shanghai, State Key Lab Med Genom, Res Ctr Med Struct Biol,Ruijin Hosp,Sch Med, Shanghai 200025, Peoples R China
7.Duke Univ, Med Ctr, Dept Med, Durham, NC 27710 USA
8.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China
推荐引用方式
GB/T 7714		 Zhu, Zi-ning,You, Chong-zhao,Yuan, Qing-ning,et al. Cryo-EM structures of GPR75 reveal an occluded orthosteric pocket challenging conventional drug discovery paradigms for an anti-obesity target[J]. ACTA PHARMACOLOGICA SINICA,2026:10.
APA Zhu, Zi-ning.,You, Chong-zhao.,Yuan, Qing-ning.,Xu, Jiu-yin.,Gu, Zong-yue.,...&Wu, Can-rong.(2026).Cryo-EM structures of GPR75 reveal an occluded orthosteric pocket challenging conventional drug discovery paradigms for an anti-obesity target.ACTA PHARMACOLOGICA SINICA,10.
MLA Zhu, Zi-ning,et al."Cryo-EM structures of GPR75 reveal an occluded orthosteric pocket challenging conventional drug discovery paradigms for an anti-obesity target".ACTA PHARMACOLOGICA SINICA (2026):10.

入库方式： OAI收割

来源：上海药物研究所

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