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Structure of the full-length glucagon class B G-protein-coupled receptor

文献类型：期刊论文

作者Zhang, Haonan1,2; Qiao, Anna1,2; Yang, Dehua1,3; Yang, Linlin4; Dai, Antao1,3; De Graaf, Chris5; Reedtz-Runge, Steffen; Dharmarajan, Venkatasubramanian6,7; Zhang, Hui1,2; Han, Gye Won8
刊名NATURE
出版日期2017-06-08
卷号546期号:7657页码:259-+
ISSN号0028-0836
DOI10.1038/nature22363
文献子类Article
英文摘要The human glucagon receptor, GCGR, belongs to the class B G-protein-coupled receptor family and plays a key role in glucose homeostasis and the pathophysiology of type 2 diabetes. Here we report the 3.0 angstrom crystal structure of full-length GCGR containing both the extracellular domain and transmembrane domain in an inactive conformation. The two domains are connected by a 12-residue segment termed the stalk, which adopts a beta-strand conformation, instead of forming an alpha-helix as observed in the previously solved structure of the GCGR transmembrane domain. The first extracellular loop exhibits a beta-hairpin conformation and interacts with the stalk to form a compact beta-sheet structure. Hydrogen-deuterium exchange, disulfide crosslinking and molecular dynamics studies suggest that the stalk and the first extracellular loop have critical roles in modulating peptide ligand binding and receptor activation. These insights into the full-length GCGR structure deepen our understanding of the signalling mechanisms of class B G-protein-coupled receptors.
WOS关键词SERIAL FEMTOSECOND CRYSTALLOGRAPHY ; CORTICOTROPIN-RELEASING-FACTOR ; LIPIDIC CUBIC PHASE ; EXTRACELLULAR DOMAINS ; DRUG DISCOVERY ; BINDING-SITE ; LIGAND ; REFINEMENT ; VALIDATION ; SOFTWARE
资助项目National Basic Research Program of China[2014CB910400] ; National Basic Research Program of China[2015CB910304] ; CAS Strategic Priority Research Program[XDB08020000] ; CAS[QYZDB-SSW-SMC024] ; National Science Foundation of China[31422017] ; National Science Foundation of China[81525024] ; National Science Foundation of China[81230076] ; National Science Foundation of China[81573479] ; National Health and Family Planning Commission[2012ZX09304-011] ; National Health and Family Planning Commission[2013ZX09401003-005] ; National Health and Family Planning Commission[2013ZX09507001] ; National Health and Family Planning Commission[2013ZX09507-002] ; Shanghai Science and Technology Development Fund[15DZ2291600] ; National Institutes of Health[R01 GM108635] ; National Institutes of Health[R21 DA042298] ; National Institutes of Health[P41GM103393] ; National Science Foundation STC award[1231306] ; GPCR Consortium[00000000] ; Shanghai local government[00000000] ; Netherlands eScience Center (NLeSC)/NWO (Enabling Technologies project: 3D-e-Chem)[027.014.201] ; US Department of Energy, Office of Science, Office of Basic Energy Sciences[DE-AC02-76SF00515]
WOS研究方向Science & Technology - Other Topics
语种英语
出版者NATURE PUBLISHING GROUP
WOS记录号WOS:000402823400031
源URL[http://119.78.100.183/handle/2S10ELR8/272613]  
专题药物发现与设计中心
中科院受体结构与功能重点实验室
新药研究国家重点实验室
药物靶标结构与功能中心
国家新药筛选中心
通讯作者Jiang, Hualiang; Wang, Ming-Wei; 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.Univ Chinese Acad Sci, 19A Yuquan Rd, Beijing 100049, Peoples R China;
3.Chinese Acad Sci, Shanghai Inst Mat Med, Natl Ctr Drug Screening, 189 Guo Shou Jing Rd, Shanghai 201203, Peoples R China;
4.Zhengzhou Univ, Sch Basic Med Sci, Dept Pharmacol, 100 Sci Ave, Zhengzhou 450001, Peoples R China;
5.Vrije Univ Amsterdam, AIMMS, Fac Sci, Div Med Chem, De Boelelaan 1108, NL-1081 HZ Amsterdam, Netherlands;
6.Novo Nordisk AS, Novo Nordisk Pk, DK-2760 Malov, Denmark;
7.Scripps Res Inst, Dept Mol Med, 130 Scripps Way, Jupiter, FL 33458 USA;
8.Univ Southern Calif, Dept Chem, Bridge Inst, 3430 S Vermont Ave, Los Angeles, CA 90089 USA;
9.SUNY Buffalo, Hauptman Woodward Inst, 700 Ellicott St, Buffalo, NY 14203 USA;
10.SLAC Natl Accelerator Lab, LCLS, Menlo Pk, CA 94025 USA;
推荐引用方式
GB/T 7714		 Zhang, Haonan,Qiao, Anna,Yang, Dehua,et al. Structure of the full-length glucagon class B G-protein-coupled receptor[J]. NATURE,2017,546(7657):259-+.
APA Zhang, Haonan.,Qiao, Anna.,Yang, Dehua.,Yang, Linlin.,Dai, Antao.,...&Wu, Beili.(2017).Structure of the full-length glucagon class B G-protein-coupled receptor.NATURE,546(7657),259-+.
MLA Zhang, Haonan,et al."Structure of the full-length glucagon class B G-protein-coupled receptor".NATURE 546.7657(2017):259-+.

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来源：上海药物研究所

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