Full-length human GLP-1 receptor structure without orthosteric ligands

doi:10.1038/s41467-020-14934-5

	Full-length human GLP-1 receptor structure without orthosteric ligands
	Wu, Fan1,2,3 ; Yang, Linlin 4; Hang, Kaini1,2,3 ; Laursen, Mette 5; Wu, Lijie2 ; Han, Gye Won 6,7; Ren, Qiansheng 8; Roed, Nikolaj Kulahin 5; Lin, Guangyao2,3 ; Hanson, Michael A.9; Jiang, Hualiang 10,11,12; Wang, Ming-Wei2,10,13,14 ; Reedtz-Runge, Steffen 5; Song, Gaojie 15,16; Stevens, Raymond C.1,2,6,7
	2020-03-09
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/s41467-020-14934-5
摘要	Glucagon-like peptide-1 receptor (GLP-1R) is a class B G protein-coupled receptor that plays an important role in glucose homeostasis and treatment of type 2 diabetes. Structures of full-length class B receptors were determined in complex with their orthosteric agonist peptides, however, little is known about their extracellular domain (ECD) conformations in the absence of orthosteric ligands, which has limited our understanding of their activation mechanism. Here, we report the 3.2 A resolution, peptide-free crystal structure of the full-length human GLP-1R in an inactive state, which reveals a unique closed conformation of the ECD. Disulfide cross-linking validates the physiological relevance of the closed conformation, while electron microscopy (EM) and molecular dynamic (MD) simulations suggest a large degree of conformational dynamics of ECD that is necessary for binding GLP-1. Our inactive structure represents a snapshot of the peptide-free GLP-1R and provides insights into the activation pathway of this receptor family.
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收录类别	SCI ; SCIE
语种	英语
资助项目	National Key Research and Development Program of China[2018YFA0507001][2018YFA0507000][2018YFA0508100] ; National Natural Science Foundation of China[31770898][31900895][81872915] ; National Science and Technology Major Project "Key New Drug Creation and Manufacturing Program" of China[2018ZX09735-001] ; China Postdoctoral Science Foundation[2017M622365]
WOS研究方向	Science & Technology - Other Topics
WOS类目	Multidisciplinary Sciences
WOS记录号	WOS:000549165100013
出版者	NATURE PUBLISHING GROUP
WOS关键词	CRYO-EM STRUCTURE ; GLUCAGON-LIKE PEPTIDE-1 ; G-PROTEIN ; DYNAMICS ; COMPLEX ; BINDING ; DOMAIN ; ACTIVATION
原始文献类型	Article
引用统计
文献类型	期刊论文
条目标识符	https://kms.shanghaitech.edu.cn/handle/2MSLDSTB/122676
专题	生命科学与技术学院_博士生 iHuman研究所_特聘教授组_Raymond Stevens组生命科学与技术学院_特聘教授组_王明伟组 iHuman研究所_科学装置(X)_膜蛋白同步辐射线站生命科学与技术学院_硕士生
通讯作者	Song, Gaojie; Stevens, Raymond C.
作者单位	1.ShanghaiTech Univ, iHuman Inst, Shanghai, Peoples R China 2.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai, Peoples R China 3.Univ Chinese Acad Sci, Beijing, Peoples R China 4.Zhengzhou Univ, Sch Basic Med Sci, Dept Pharmacol, Zhengzhou, Peoples R China 5.Novo Nordisk AS, Novo Nordisk Pk, Copenhagen, Denmark 6.Univ Southern Calif, USC Michelson Ctr Convergent Biosci, Bridge Inst, Dept Biol Sci, Los Angeles, CA 90007 USA 7.Univ Southern Calif, USC Michelson Ctr Convergent Biosci, Bridge Inst, Dept Chem, Los Angeles, CA 90007 USA 8.Novo Nordisk Res Ctr, Beijing, Peoples R China 9.GPCR Consortium, San Marcos, CA USA 10.Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, Shanghai, Peoples R China 11.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai, Peoples R China 12.Chinese Acad Sci, Drug Discovery & Design Ctr, Shanghai Inst Mat Med, Shanghai, Peoples R China 13.Chinese Acad Sci, Natl Ctr Drug Screening, Shanghai Inst Mat Med, Shanghai, Peoples R China 14.Fudan Univ, Sch Pharm, Shanghai, Peoples R China 15.East China Normal Univ, Inst Biomed Sci, Shanghai Key Lab Regulatory Biol, Shanghai, Peoples R China 16.East China Normal Univ, Sch Life Sci, Shanghai, Peoples R China
第一作者单位	iHuman研究所; 生命科学与技术学院
通讯作者单位	iHuman研究所; 生命科学与技术学院
第一作者的第一单位	iHuman研究所
推荐引用方式 GB/T 7714	Wu, Fan,Yang, Linlin,Hang, Kaini,et al. Full-length human GLP-1 receptor structure without orthosteric ligands[J]. NATURE COMMUNICATIONS,2020,11(1).
APA	Wu, Fan.,Yang, Linlin.,Hang, Kaini.,Laursen, Mette.,Wu, Lijie.,...&Stevens, Raymond C..(2020).Full-length human GLP-1 receptor structure without orthosteric ligands.NATURE COMMUNICATIONS,11(1).
MLA	Wu, Fan,et al."Full-length human GLP-1 receptor structure without orthosteric ligands".NATURE COMMUNICATIONS 11.1(2020).