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

doi:10.1101/2023.11.03.565472

	Mechanisms of ligand recognition and activation of melanin-concentrating hormone receptors
	He, Qian 1,2; Yuan, Qingning 1,3; Shan, Hong 1; Wu, Canrong 1; Gu, Yimin 1; Wu, Kai 1; Hu, Wen 1; Zhang, Yumu1,4 ; Xu, H. Eric 1,2; Zhao, Li-Hua 1,2
	2023-11-03
状态	已发表
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 can couple with multiple G-proteins, including Gi/o, Gq/11, and Gs, while MCHR2 only couple to Gq/11. Here we present cryo-electron microscopy structures of MCH-activated MCHR1 with Gi and MCH-activated MCHR2 with Gq complexes, at the global resolutions of 3.01 Ã and 2.40 Ã , respectively. These structures reveal that MCH adopts a consistent cysteine-mediated hairpin loop configuration in 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, offering a structured foundation for targeted drug design.
语种	英语
DOI	10.1101/2023.11.03.565472
相关网址	查看原文
出处	bioRxiv
收录类别	PPRN.PPRN
WOS记录号	PPRN:85975429
WOS类目	Biochemistry & Molecular Biology
资助项目	Natural Science Foundation of Shanghai["23ZR1475200","XDB37030103","32071203","2019SHZDZX02","2018325","2018YFA0507002","LG-GG-202204-01","SKLDR-2023-TT-04"] ; CAS StrateGic Priority Research Program["Y2022078","32130022","2019YFA0904200"] ; National Natural Science Foundation of China[82121005]
文献类型	预印本
条目标识符	https://kms.shanghaitech.edu.cn/handle/2MSLDSTB/381339
专题	生命科学与技术学院生命科学与技术学院_博士生
通讯作者	Xu, H. Eric; Zhao, Li-Hua
作者单位	1.Chinese Acad Sci, Shanghai Inst Mat Med, Ctr Struct & Funct Drug Targets, State Key Lab Drug Res, Shanghai, Peoples R China 2.Univ Chinese Acad Sci, Beijing 100049, Peoples R China 3.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing, Peoples R China 4.Shanghai Tech Univ, Sch Life Sci & Technol, Shanghai 201210, 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. 2023.