Structure of the glucagon receptor in complex with a glucagon analogue

doi:10.1038/nature25153

KMS > iHuman研究所

	Structure of the glucagon receptor in complex with a glucagon analogue
	Zhang, Haonan 1,2,3; Qiao, Anna 1,2,3; Yang, Linlin 4; Van Eps, Ned 5; Frederiksen, Klaus S.6; Yang, Dehua 1,7; Dai, Antao 1,7; Cai, Xiaoqing 1,7; Zhang, Hui 1,3; Yi, Cuiying 1; Cao, Can 3,8; He, Lingli 8; Yang, Huaiyu 9,10; Lau, Jesper 6; Ernst, Oliver P.5,11; Hanson, Michael A.12; Stevens, Raymond C.13,14 ; Wang, Ming-Wei1,3,7,14,15 ; Reedtz-Runge, Steffen 6; Jiang, Hualiang 1,2,16; Zhao, Qiang 1,2,3,17; Wu, Beili1,3,14,17
	2018-01-04
发表期刊	NATURE (IF:50.5[JCR-2023],54.4[5-Year])
ISSN	0028-0836
卷号	553 期号:7686 页码:106-+
发表状态	已发表
DOI	10.1038/nature25153
摘要	Class B G-protein-coupled receptors (GPCRs), which consist of an extracellular domain (ECD) and a transmembrane domain (TMD), respond to secretin peptides to play a key part in hormonal homeostasis, and are important therapeutic targets for a variety of diseases(1-8). Previous work(9-11) has suggested that peptide ligands bind to class B GPCRs according to a two-domain binding model, in which the C-terminal region of the peptide targets the ECD and the N-terminal region of the peptide binds to the TMD binding pocket. Recently, three structures of class B GPCRs in complex with peptide ligands have been solved(12-14). These structures provide essential insights into peptide ligand recognition by class B GPCRs. However, owing to resolution limitations, the specific molecular interactions for peptide binding to class B GPCRs remain ambiguous. Moreover, these previously solved structures have different ECD conformations relative to the TMD, which introduces questions regarding inter-domain conformational flexibility and the changes required for receptor activation. Here we report the 3.0 angstrom-resolution crystal structure of the full-length human glucagon receptor (GCGR) in complex with a glucagon analogue and partial agonist, NNC1702. This structure provides molecular details of the interactions between GCGR and the peptide ligand. It reveals a marked change in the relative orientation between the ECD and TMD of GCGR compared to the previously solved structure of the inactive GCGR-NNC0640-mAb1 complex. Notably, the stalk region and the first extracellular loop undergo major conformational changes in secondary structure during peptide binding, forming key interactions with the peptide. We further propose a dual-binding-site trigger model for GCGR activation-which requires conformational changes of the stalk, first extracellular loop and TMD-that extends our understanding of the previously established two-domain peptide-binding model of class B GPCRs.
收录类别	SCI ; SCIE
语种	英语
资助项目	Special Program for Applied Research on Super Computation of the NSFC-Guangdong Joint Fund[U1501501]
WOS研究方向	Science & Technology - Other Topics
WOS类目	Multidisciplinary Sciences
WOS记录号	WOS:000419769300039
出版者	NATURE PUBLISHING GROUP
WOS关键词	PROTEIN-COUPLED RECEPTOR ; CYCLASE-ACTIVATING POLYPEPTIDE ; CRYO-EM STRUCTURE ; CLASS-B GPCRS ; GLP-1 RECEPTOR ; PEPTIDE-1 RECEPTOR ; LIGAND-BINDING ; DOMAIN ; ANTAGONISTS ; REFINEMENT
原始文献类型	Article
引用统计	正在获取...
文献类型	期刊论文
条目标识符	https://kms.shanghaitech.edu.cn/handle/2MSLDSTB/16217
专题	iHuman研究所 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_王明伟组生命科学与技术学院_特聘教授组_吴蓓丽组
通讯作者	Zhao, Qiang; Wu, Beili
作者单位	1.Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China 2.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China 3.Univ Chinese Acad Sci, 19A Yuquan Rd, Beijing 100049, Peoples R China 4.Zhengzhou Univ, Sch Basic Med Sci, Dept Pharmacol, 100 Sci Ave, Zhengzhou 450001, Henan, Peoples R China 5.Univ Toronto, Dept Biochem, Toronto, ON M5S 1A8, Canada 6.Novo Nordisk AS, Novo Nordisk Pk, DK-2760 Malov, Denmark 7.Chinese Acad Sci, Shanghai Inst Mat Med, Natl Ctr Drug Screening, 189 Guo Shou Jing Rd, Shanghai 201203, Peoples R China 8.Chinese Acad Sci, Inst Biophys, CAS Ctr Excellence Biomacromol, Natl Ctr Prot Sci,Natl Lab Biomacromol, Beijing 100101, Peoples R China 9.East China Normal Univ, Inst Biomed Sci, Shanghai Key Lab Regulatory Biol, 500 Dongchuan Rd, Shanghai 200241, Peoples R China 10.East China Normal Univ, Sch Life Sci, 500 Dongchuan Rd, Shanghai 200241, Peoples R China 11.Univ Toronto, Dept Mol Genet, Toronto, ON M5S 1A8, Canada 12.GPCR Consortium, San Marcos, CA 92078 USA 13.ShanghaiTech Univ, iHuman Inst, 393 Hua Xia Zhong Rd, Shanghai 201210, Peoples R China 14.ShanghaiTech Univ, Sch Life Sci & Technol, 393 Hua Xia Zhong Rd, Shanghai 201210, Peoples R China 15.Fudan Univ, Sch Pharm, 826 Zhangheng Rd, Shanghai 201203, Peoples R China 16.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Drug Discovery & Design Ctr, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China 17.Chinese Acad Sci, CAS Ctr Excellence Biomacromol, Beijing 100101, 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	Zhang, Haonan,Qiao, Anna,Yang, Linlin,et al. Structure of the glucagon receptor in complex with a glucagon analogue[J]. NATURE,2018,553(7686):106-+.
APA	Zhang, Haonan.,Qiao, Anna.,Yang, Linlin.,Van Eps, Ned.,Frederiksen, Klaus S..,...&Wu, Beili.(2018).Structure of the glucagon receptor in complex with a glucagon analogue.NATURE,553(7686),106-+.
MLA	Zhang, Haonan,et al."Structure of the glucagon receptor in complex with a glucagon analogue".NATURE 553.7686(2018):106-+.