机构：[1]Department of Biotherapy, Cancer Center and Kidney Research Institute, State Key Laboratory of Biotherapy and National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China四川大学华西医院[2]Department of Ophthalmology and Research Laboratory of Macular Disease, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China四川大学华西医院[3]The Chinese Academy of Sciences Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui 230027, China[4]Institute of Health and Medicine, Hefei Comprehensive National Science Center, Hefei, Anhui 230601, China[5]Key Laboratory of Drug Targeting and Drug Delivery System of Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu, Sichuan 610041, China[6]Frontier Medical Center Tianfu Jincheng Laboratory, Chengdu, Sichuan 610212, China
GPR34 is a functional G-protein-coupled receptor of Lysophosphatidylserine (LysoPS), and has pathogenic roles in numerous diseases, yet remains poorly targeted. We herein report a cryo-electron microscopy (cryo-EM) structure of GPR34 bound with LysoPS (18:1) and Gi protein, revealing a unique ligand recognition mode with the negatively charged head group of LysoPS occupying a polar cavity formed by TM3, 6 and 7, and the hydrophobic tail of LysoPS residing in a lateral open hydrophobic groove formed by TM3-5. Virtual screening and subsequent structural optimization led to the identification of a highly potent and selective antagonist (YL-365). Design of fusion proteins allowed successful determination of the challenging cryo-EM structure of the inactive GPR34 complexed with YL-365, which revealed the competitive binding of YL-365 in a portion of the orthosteric binding pocket of GPR34 and the antagonist-binding-induced allostery in the receptor, implicating the inhibition mechanism of YL-365. Moreover, YL-365 displayed excellent activity in a neuropathic pain model without obvious toxicity. Collectively, this study offers mechanistic insights into the endogenous agonist recognition and antagonist inhibition of GPR34, and provides proof of concept that targeting GPR34 represents a promising strategy for disease treatment.
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出版当年[2023]版：
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最新[2023]版：
大类|1 区综合性期刊
小类|1 区综合性期刊
第一作者：
第一作者机构：[1]Department of Biotherapy, Cancer Center and Kidney Research Institute, State Key Laboratory of Biotherapy and National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China[2]Department of Ophthalmology and Research Laboratory of Macular Disease, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
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通讯作者：
通讯机构：[1]Department of Biotherapy, Cancer Center and Kidney Research Institute, State Key Laboratory of Biotherapy and National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China[3]The Chinese Academy of Sciences Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui 230027, China[4]Institute of Health and Medicine, Hefei Comprehensive National Science Center, Hefei, Anhui 230601, China[6]Frontier Medical Center Tianfu Jincheng Laboratory, Chengdu, Sichuan 610212, China
推荐引用方式(GB/T 7714)：
Xia Anjie,Yong Xihao,Zhang Changbin,et al.Cryo-EM structures of human GPR34 enable the identification of selective antagonists[J].Proceedings of the National Academy of Sciences of the United States of America.2023,120(39):e2308435120.doi:10.1073/pnas.2308435120.
APA：
Xia Anjie,Yong Xihao,Zhang Changbin,Lin Guifeng,Jia Guowen...&Yang Shengyong.(2023).Cryo-EM structures of human GPR34 enable the identification of selective antagonists.Proceedings of the National Academy of Sciences of the United States of America,120,(39)
MLA：
Xia Anjie,et al."Cryo-EM structures of human GPR34 enable the identification of selective antagonists".Proceedings of the National Academy of Sciences of the United States of America 120..39(2023):e2308435120
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