Human GLP-1 receptor transmembrane domain structure in complex with allosteric modulators

doi:10.1038/nature22378

KMS > iHuman研究所

	Human GLP-1 receptor transmembrane domain structure in complex with allosteric modulators
	Song, Gaojie1 ; Yang, Dehua 2,3; Wang, Yuxia1 ; de Graaf, Chris 4; Zhou, Qingtong1 ; Jiang, Shanshan 5; Liu, Kaiwen1,6,7 ; Cai, Xiaoqing 2,3; Dai, Antao 2,3; Lin, Guangyao6 ; Liu, Dongsheng1 ; Wu, Fan1,6,7 ; Wu, Yiran1 ; Zhao, Suwen1,6 ; Ye, Li 5; Han, Gye Won 8; Lau, Jesper 9; Wu, Beili6,7,10 ; Hanson, Michael A.11; Liu, Zhi-Jie1,6,12 ; Wang, Ming-Wei2,3,5,6 ; Stevens, Raymond C.1,6
	2017-06-08
发表期刊	NATURE (IF:50.5[JCR-2023],54.4[5-Year])
ISSN	0028-0836
卷号	546 期号:7657 页码:312-+
发表状态	已发表
DOI	10.1038/nature22378
摘要	The glucagon-like peptide-1 receptor (GLP-1R) and the glucagon receptor (GCGR) are members of the secretin-like class B family of G-protein-coupled receptors (GPCRs) and have opposing physiological roles in insulin release and glucose homeostasis(1). The treatment of type 2 diabetes requires positive modulation of GLP-1R to inhibit glucagon secretion and stimulate insulin secretion in a glucose-dependent manner(2). Here we report crystal structures of the human GLP-1R transmembrane domain in complex with two different negative allosteric modulators, PF-06372222 and NNC0640, at 2.7 and 3.0 angstrom resolution, respectively. The structures reveal a common binding pocket for negative allosteric modulators, present in both GLP-1R and GCGR(3) and located outside helices V-VII near the intracellular half of the receptor. The receptor is in an inactive conformation with compounds that restrict movement of the intracellular tip of helix VI, a movement that is generally associated with activation mechanisms in class A GPCRs(4-6). Molecular modelling and mutagenesis studies indicate that agonist positive allosteric modulators target the same general region, but in a distinct sub-pocket at the interface between helices V and VI, which may facilitate the formation of an intracellular binding site that enhances G-protein coupling.
收录类别	SCI
语种	英语
资助项目	National Key Research and Development Program of China[2016YCF0905902]
WOS研究方向	Science & Technology - Other Topics
WOS类目	Multidisciplinary Sciences
WOS记录号	WOS:000402823400042
出版者	NATURE PUBLISHING GROUP
WOS关键词	GLUCAGON-LIKE PEPTIDE-1 ; PROTEIN-COUPLED RECEPTORS ; MOLECULAR SIMULATION ; CRYSTAL-STRUCTURE ; FORCE-FIELD ; LIGAND ; ANTAGONIST ; AGONIST ; BINDING ; DETERMINANTS
原始文献类型	Article
通讯作者	Liu, Zhi-Jie ; Wang, Ming-Wei ; Stevens, Raymond C.
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/1335
专题	iHuman研究所生命科学与技术学院 iHuman研究所_特聘教授组_Andrej Sali组 iHuman研究所_特聘教授组_Raymond Stevens组 iHuman研究所_特聘教授组_Kurt Wuthrich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 iHuman研究所_PI研究组_刘志杰组 iHuman研究所_PI研究组_赵素文组生命科学与技术学院_博士生
通讯作者	Liu, Zhi-Jie; Wang, Ming-Wei; Stevens, Raymond C.
作者单位	1.ShanghaiTech Univ, iHuman Inst, 393 Middle Huaxia Rd, Shanghai 201210, Peoples R China 2.Chinese Acad Sci, Shanghai Inst Mat Med, Natl Ctr Drug Screening, 189 Guo Shou Jing Rd, Shanghai 201203, Peoples R China 3.Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, 189 Guo Shou Jing Rd, Shanghai 201203, Peoples R China 4.Vrije Univ Amsterdam, Fac Sci, Div Med Chem, AIMMS, De Boelelaan 1108, NL-1081 HZ Amsterdam, Netherlands 5.Fudan Univ, Sch Pharm, 826 Zhang Heng Rd, Shanghai 201203, Peoples R China 6.ShanghaiTech Univ, Sch Life Sci & Technol, 393 Middle Huaxia Rd, Shanghai 201210, Peoples R China 7.Univ Chinese Acad Sci, 19A Yuquan Rd, Beijing 100049, Peoples R China 8.Univ Southern Calif, Bridge Inst, Dept Chem, 3430 S Vermont Ave, Los Angeles, CA 90089 USA 9.Novo Nordisk, DK-2760 Malov, Denmark 10.Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China 11.GPCR Consortium, San Marcos, CA 92078 USA 12.Kunming Med Univ, Inst Mol & Clin Med, Kunming 650500, Peoples R China
第一作者单位	iHuman研究所
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	Song, Gaojie,Yang, Dehua,Wang, Yuxia,et al. Human GLP-1 receptor transmembrane domain structure in complex with allosteric modulators[J]. NATURE,2017,546(7657):312-+.
APA	Song, Gaojie.,Yang, Dehua.,Wang, Yuxia.,de Graaf, Chris.,Zhou, Qingtong.,...&Stevens, Raymond C..(2017).Human GLP-1 receptor transmembrane domain structure in complex with allosteric modulators.NATURE,546(7657),312-+.
MLA	Song, Gaojie,et al."Human GLP-1 receptor transmembrane domain structure in complex with allosteric modulators".NATURE 546.7657(2017):312-+.