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

文献类型：期刊论文

作者Zhou, Fulai4,5; Zhang, Huibing6,7; Cong, Zhaotong8; Zhao, Li-Hua4; Zhou, Qingtong9; Mao, Chunyou6,7; Cheng, Xi10,11; Shen, Dan-Dan6,7; Cai, Xiaoqing4,5; Ma, Cheng6,7
刊名NATURE COMMUNICATIONS
出版日期2020-10-15
卷号11期号:1页码:10
ISSN号2041-1723
DOI10.1038/s41467-020-18945-0
通讯作者Yang, Dehua(dhyang@simm.ac.cn) ; Xu, H. Eric(eric.xu@simm.ac.cn) ; Zhang, Yan(zhang_yan@zju.edu.cn) ; Wang, Ming-Wei(mwwang@simm.ac.cn)
英文摘要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.
WOS关键词CRYO-EM STRUCTURE ; GLP-1 RECEPTOR ; MOLECULAR-BASIS ; GHRH ; RECOGNITION ; COMPLEX ; MECHANISM ; DYNAMICS ; INSIGHTS ; DOMAIN
资助项目National Natural Science Foundation of China[81872915] ; National Natural Science Foundation of China[81922071] ; National Natural Science Foundation of China[81773792] ; National Natural Science Foundation of China[81973373] ; National Natural Science Foundation of China[21704064] ; National Natural Science Foundation of China[31770796] ; National Natural Science Foundation of China[31971178] ; National Science and Technology Major Project of ChinaKey New Drug Creation and Manufacturing Program[2018ZX09735-001] ; National Science and Technology Major Project of ChinaKey New Drug Creation and Manufacturing Program[2018ZX09711002-002-005] ; National Science and Technology Major Project of ChinaKey New Drug Creation and Manufacturing Program[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] ; SA-SIBS Scholarship Program ; Novo Nordisk-CAS Research Fund[NNCAS-2017-1-CC]
WOS研究方向Science & Technology - Other Topics
语种英语
WOS记录号WOS:000582681400017
出版者NATURE RESEARCH
源URL[http://119.78.100.183/handle/2S10ELR8/291030]  
专题新药研究国家重点实验室
通讯作者Yang, Dehua; Xu, H. Eric; Zhang, Yan; Wang, Ming-Wei
作者单位1.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
2.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai 201210, Peoples R China
3.Fudan Univ, Sch Basic Med Sci, Shanghai 200032, Peoples R China
4.Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, Shanghai 201203, Peoples R China
5.Chinese Acad Sci, Shanghai Inst Mat Med, Natl Ctr Drug Screening, Shanghai 201203, Peoples R China
6.Zhejiang Univ, Sir Run Run Shaw Hosp, Sch Med, Dept Biophys, Hangzhou 310058, Peoples R China
7.Zhejiang Univ, Sir Run Run Shaw Hosp, Sch Med, Dept Pathol, Hangzhou 310058, Peoples R China
8.Fudan Univ, Sch Pharm, Shanghai 201203, Peoples R China
9.ShanghaiTech Univ, iHuman Inst, Shanghai 201210, Peoples R China
10.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		 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):10.
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),10.
MLA Zhou, Fulai,et al."Structural basis for activation of the growth hormone-releasing hormone receptor".NATURE COMMUNICATIONS 11.1(2020):10.

入库方式： OAI收割

来源：上海药物研究所

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