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

被引：155

作者：

Zhang, Haonan ^{[1
,2
]}

Qiao, Anna ^{[1
,2
]}

Yang, Dehua ^{[1
,3
]}

Yang, Linlin ^{[4
]}

Dai, Antao ^{[1
,3
]}

De Graaf, Chris ^{[5
]}

Reedtz-Runge, Steffen

Dharmarajan, Venkatasubramanian ^{[6
,7
]}

Zhang, Hui ^{[1
,2
]}

Han, Gye Won ^{[8
]}

Grant, Thomas D. ^{[9
]}

Sierra, Raymond G. ^{[10
]}

Weierstall, Uwe ^{[11
]}

Nelson, Garrett ^{[11
]}

Liu, Wei ^{[12
]}

Wu, Yanhong ^{[1
,2
,13
]}

Ma, Limin ^{[1
]}

Cai, Xiaoqing ^{[1
,3
]}

Lin, Guangyao ^{[1
,2
,3
,13
]}

Wu, Xiaoai ^{[14
]}

Geng, Zhi ^{[15
]}

Dong, Yuhui ^{[15
]}

Song, Gaojie ^{[16
]}

Griffin, Patrick R. ^{[7
]}

Lau, Jesper ^{[6
]}

Chrezov, Vadim ^{[8
]}

Yang, Huaiyu ^{[17
]}

Hanson, Michael A. ^{[18
]}

Stevens, Raymond C. ^{[13
,16
]}

Zhao, Qiang ^{[1
,2
,19
,20
]}

Jiang, Hualiang ^{[1
,17
,19
]}

Wang, Ming-Wei ^{[1
,3
,13
,21
]}

Wu, Beili ^{[1
,2
,13
,20
]}

机构：

[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

[11] Arizona State Univ, Dept Phys, Tempe, AZ 85287 USA

[12] Arizona State Univ, Biodesign Inst, Sch Mol Sci, Biodesign Ctr Appl Struct Discovery, Tempe, AZ 85287 USA

[13] ShanghaiTech Univ, Sch Life Sci & Technol, 393 Hua Xia Zhong Rd, Shanghai 201210, Peoples R China

[14] Novo Nordisk Res Ctr China, 20 Life Sci Pk Rd, Beijing 102206, Peoples R China

[15] Chinese Acad Sci, Beijing Synchrotron Radiat Facil, Inst High Energy Phys, Beijing 100049, Peoples R China

[16] ShanghaiTech Univ, iHuman Inst, 393 Hua Xia Zhong Rd, Shanghai 201210, Peoples R China

[17] Chinese Acad Sci, Shanghai Inst Mat Med, Drug Discovery & Design Ctr, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China

[18] GPCR Consortium, San Marcos, CA 92078 USA

[19] Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China

[20] Chinese Acad Sci, CAS Ctr Excellence Biomacromol, Beijing 100101, Peoples R China

[21] Fudan Univ, Sch Pharm, 826 Zhangheng Rd, Shanghai 201203, Peoples R China

来源：

NATURE | 2017年 / 546卷 / 7657期

基金：

美国国家科学基金会; 美国国家卫生研究院;

关键词：

SERIAL FEMTOSECOND CRYSTALLOGRAPHY; CORTICOTROPIN-RELEASING-FACTOR; LIPIDIC CUBIC PHASE; EXTRACELLULAR DOMAINS; DRUG DISCOVERY; BINDING-SITE; LIGAND; REFINEMENT; VALIDATION; SOFTWARE;

D O I：

10.1038/nature22363

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

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.

引用

页码：259 / +

页数：18

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