Structural basis for activation of the growth hormone-releasing hormone receptor

doi:10.1038/s41467-020-18945-0

	Structural basis for activation of the growth hormone-releasing hormone receptor
	Zhou, Fulai 1,2; Zhang, Huibing 3,4; Cong, Zhaotong 5; Zhao, Li-Hua 1; Zhou, Qingtong6 ; Mao, Chunyou 3,4; Cheng, Xi 7,8; Shen, Dan-Dan 3,4; Cai, Xiaoqing 1,2; Ma, Cheng 3,4; Wang, Yuzhe 1,2,9; Dai, Antao 1,2; Zhou, Yan 1,2; Sun, Wen 1,2,9; Zhao, Fenghui 5; Zhao, Suwen6,10 ; Jiang, Hualiang7,8,9,10 ; Jiang, Yi 1; Yang, Dehua 1,2,9; Xu, H. Eric 1,9; Zhang, Yan 3,4; Wang, Ming-Wei1,2,5,9,10,11
	2020-10-15
发表期刊	NATURE COMMUNICATIONS
ISSN	2041-1723
卷号	11 期号:1
发表状态	已发表
DOI	10.1038/s41467-020-18945-0
摘要	Growth hormone-releasing hormone (GHRH) regulates the secretion of growth hormone that virtually controls metabolism and growth of every tissue through its binding to the cognate receptor (GHRHR). Malfunction in GHRHR signaling is associated with abnormal growth, making GHRHR an attractive therapeutic target against dwarfism (e.g., isolated growth hormone deficiency, IGHD), gigantism, lipodystrophy and certain cancers. Here, we report the cryo-electron microscopy (cryo-EM) structure of the human GHRHR bound to its endogenous ligand and the stimulatory G protein at 2.6 angstrom. This high-resolution structure reveals a characteristic hormone recognition pattern of GHRH by GHRHR, where the alpha-helical GHRH forms an extensive and continuous network of interactions involving all the extracellular loops (ECLs), all the transmembrane (TM) helices except TM4, and the extracellular domain (ECD) of GHRHR, especially the N-terminus of GHRH that engages a broad set of specific interactions with the receptor. Mutagenesis and molecular dynamics (MD) simulations uncover detailed mechanisms by which IGHD-causing mutations lead to the impairment of GHRHR function. Our findings provide insights into the molecular basis of peptide recognition and receptor activation, thereby facilitating the development of structure-based drug discovery and precision medicine.
URL	查看原文
收录类别	SCI ; SCIE
语种	英语
资助项目	National Natural Science Foundation of China[81872915][81922071][81773792][81973373][21704064][31770796][31971178] ; National Science and Technology Major Project of ChinaKey New Drug Creation and Manufacturing Program[2018ZX09735-001][2018ZX09711002-002-005][2018ZX09711002-002-002] ; Shanghai Municipal Science and Technology Major Project[2019SHZDZX02] ; Ministry of Science and Technology of China[XDB08020303] ; National Key R&D Program of China[2018YFA0507000] ; Zhejiang Province Science Fund for Distinguished Young Scholars[LR19H310001] ; Shanghai Science and Technology Development Fund[18ZR1447800] ; Young Innovator Association of CAS[2018325] ; Novo Nordisk-CAS Research Fund[NNCAS-2017-1-CC]
WOS研究方向	Science & Technology - Other Topics
WOS类目	Multidisciplinary Sciences
WOS记录号	WOS:000582681400017
出版者	NATURE RESEARCH
引用统计
文献类型	期刊论文
条目标识符	https://kms.shanghaitech.edu.cn/handle/2MSLDSTB/123943
专题	iHuman研究所_PI研究组_赵素文组 iHuman研究所_特聘教授组_Andrej Sali组生命科学与技术学院_特聘教授组_王明伟组免疫化学研究所_特聘教授组_蒋华良组
通讯作者	Yang, Dehua; Xu, H. Eric; Zhang, Yan; Wang, Ming-Wei
作者单位	1.Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, Shanghai 201203, Peoples R China 2.Chinese Acad Sci, Shanghai Inst Mat Med, Natl Ctr Drug Screening, Shanghai 201203, Peoples R China 3.Zhejiang Univ, Sir Run Run Shaw Hosp, Sch Med, Dept Biophys, Hangzhou 310058, Peoples R China 4.Zhejiang Univ, Sir Run Run Shaw Hosp, Sch Med, Dept Pathol, Hangzhou 310058, Peoples R China 5.Fudan Univ, Sch Pharm, Shanghai 201203, Peoples R China 6.ShanghaiTech Univ, iHuman Inst, Shanghai 201210, Peoples R China 7.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China 8.Chinese Acad Sci, Shanghai Inst Mat Med, Drug Discovery & Design Ctr, Shanghai 201203, Peoples R China 9.Univ Chinese Acad Sci, Beijing 100049, Peoples R China 10.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai 201210, Peoples R China 11.Fudan Univ, Sch Basic Med Sci, Shanghai 200032, Peoples R China
通讯作者单位	生命科学与技术学院
推荐引用方式 GB/T 7714	Zhou, Fulai,Zhang, Huibing,Cong, Zhaotong,et al. Structural basis for activation of the growth hormone-releasing hormone receptor[J]. NATURE COMMUNICATIONS,2020,11(1).
APA	Zhou, Fulai.,Zhang, Huibing.,Cong, Zhaotong.,Zhao, Li-Hua.,Zhou, Qingtong.,...&Wang, Ming-Wei.(2020).Structural basis for activation of the growth hormone-releasing hormone receptor.NATURE COMMUNICATIONS,11(1).
MLA	Zhou, Fulai,et al."Structural basis for activation of the growth hormone-releasing hormone receptor".NATURE COMMUNICATIONS 11.1(2020).