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Mechanisms of ligand recognition and activation of melanin-concentrating hormone receptors

文献类型：期刊论文

作者He, Qian2,3; Yuan, Qingning1; Shan, Hong3; Wu, Canrong3; Gu, Yimin3; Wu, Kai3; Hu, Wen3; Zhang, Yumu3; He, Xinheng2,3; Xu, H. Eric2,3
刊名CELL DISCOVERY
出版日期2024-05-07
卷号10期号:1页码:13
DOI10.1038/s41421-024-00679-8
通讯作者Xu, H. Eric(eric.xu@simm.ac.cn) ; Zhao, Li-Hua(zhaolihuawendy@simm.ac.cn)
英文摘要Melanin-concentrating hormone (MCH) is a cyclic neuropeptide that regulates food intake, energy balance, and other physiological functions by stimulating MCHR1 and MCHR2 receptors, both of which are class A G protein-coupled receptors. MCHR1 predominately couples to inhibitory G protein, Gi/o, and MCHR2 can only couple to Gq/11. Here we present cryo-electron microscopy structures of MCH-activated MCHR1 with Gi and MCH-activated MCHR2 with Gq at the global resolutions of 3.01 & Aring; and 2.40 & Aring;, respectively. These structures reveal that MCH adopts a consistent cysteine-mediated hairpin loop configuration when bound to both receptors. A central arginine from the LGRVY core motif between the two cysteines of MCH penetrates deeply into the transmembrane pocket, triggering receptor activation. Integrated with mutational and functional insights, our findings elucidate the molecular underpinnings of ligand recognition and MCH receptor activation and offer a structural foundation for targeted drug design.
WOS关键词ENERGY-BALANCE ; MCH1 RECEPTOR ; G-PROTEINS ; MICE ; HORMONE-RECEPTOR-1 ; STABILIZATION ; SUBTYPE-1 ; SYSTEM
资助项目Natural Science Foundation of Shanghai (23ZR1475200 to LHZ); National Natural Science Foundation of China (32071203 to LHZ, 32130022 and 82121005 to H.E.X.); CAS StrateGic Priority Research Program (XDB37030103 to H.E.X.); Shanghai Municipal Science and Te ; Chinese Academy of Sciences[23ZR1475200] ; Natural Science Foundation of Shanghai[32071203] ; Natural Science Foundation of Shanghai[32130022] ; Natural Science Foundation of Shanghai[82121005] ; National Natural Science Foundation of China[Y2022078] ; Young Innovator Association of CAS[XDB37030103] ; CAS StrateGic Priority Research Program ; Shanghai Municipal Science and Technology Major Project[2022YFC2703105] ; Shanghai Municipal Science and Technology Major Project[2019YFA0904200] ; Shanghai Municipal Science and Technology Major Project[LG-GG-202204-01] ; National Key R&D Program of China[SKLDR-2023-TT-04] ; State Key Laboratory of Drug Research
WOS研究方向Cell Biology
语种英语
WOS记录号WOS:001214762800001
出版者SPRINGERNATURE
源URL[http://119.78.100.183/handle/2S10ELR8/310876]  
专题新药研究国家重点实验室
通讯作者Xu, H. Eric; Zhao, Li-Hua
作者单位1.Nanjing Univ Chinese Med, Coll Pharm, Nanjing, Jiangsu, Peoples R China
2.Univ Chinese Acad Sci, Beijing, Peoples R China
3.Chinese Acad Sci, Shanghai Inst Mat Med, Ctr Struct & Funct Drug Targets, State Key Lab Drug Res, Shanghai, Peoples R China
推荐引用方式
GB/T 7714		 He, Qian,Yuan, Qingning,Shan, Hong,et al. Mechanisms of ligand recognition and activation of melanin-concentrating hormone receptors[J]. CELL DISCOVERY,2024,10(1):13.
APA He, Qian.,Yuan, Qingning.,Shan, Hong.,Wu, Canrong.,Gu, Yimin.,...&Zhao, Li-Hua.(2024).Mechanisms of ligand recognition and activation of melanin-concentrating hormone receptors.CELL DISCOVERY,10(1),13.
MLA He, Qian,et al."Mechanisms of ligand recognition and activation of melanin-concentrating hormone receptors".CELL DISCOVERY 10.1(2024):13.

入库方式： OAI收割

来源：上海药物研究所

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