Structural basis of Gs and Gi recognition by the human glucagon receptor

被引：112

作者：

Qiao, Anna ^{[1
,2
,3
]}

Han, Shuo ^{[1
,2
]}

Li, Xinmei ^{[3
,4
]}

Li, Zhixin ^{[5
]}

Zhao, Peishen ^{[6
,7
]}

Dai, Antao ^{[1
,8
]}

Chang, Rulve ^{[5
]}

Tai, Linhua ^{[3
,4
]}

Tan, Qiuxiang ^{[1
,2
]}

Chu, Xiaojing ^{[1
,2
]}

Ma, Limin ^{[1
,2
]}

Thorsen, Thor Seneca ^{[9
]}

Reedtz-Runge, Steffen ^{[9
]}

Yang, Dehua ^{[1
,8
]}

Wang, Ming-Wei ^{[1
,3
,5
,8
,10
]}

Sexton, Patrick M. ^{[5
,6
,7
]}

Wootten, Denise ^{[5
,6
,7
]}

Sun, Fei ^{[3
,4
,11
]}

Zhao, Qiang ^{[2
,3
,12
]}

Wu, Beili ^{[1
,3
,10
,12
]}

机构：

[1] Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, Shanghai 201203, Peoples R China

[2] Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China

[3] Univ Chinese Acad Sci, Beijing 100049, Peoples R China

[4] Chinese Acad Sci, Natl Lab Biomacromol, Natl Ctr Prot Sci Beijing, CAS Ctr Excellence Biomacromol,Inst Biophys, Beijing 100101, Peoples R China

[5] Fudan Univ, Sch Pharm, Shanghai 201203, Peoples R China

[6] Monash Univ, Drug Discovery Biol, Monash Inst Pharmaceut Sci, Parkville, Vic 3052, Australia

[7] Monash Univ, Dept Pharmacol, Monash Inst Pharmaceut Sci, Parkville, Vic 3052, Australia

[8] Chinese Acad Sci, Natl Ctr Drug Screening, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China

[9] Novo Nordisk AS, DK-2760 Malov, Denmark

[10] ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai 201210, Peoples R China

[11] Chinese Acad Sci, Ctr Biol Imaging, Inst Biophys, Beijing 100101, Peoples R China

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

来源：

SCIENCE | 2020年 / 367卷 / 6484期

基金：

国家重点研发计划; 美国国家科学基金会; 英国医学研究理事会;

关键词：

CRYO-EM STRUCTURE; GLP-1; RECEPTOR; SPECIFICITY; ACTIVATION; COMPLEX; CELLS; CA2+;

D O I：

10.1126/science.aaz5346

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：

Class B G protein-coupled receptors, an important class of therapeutic targets, signal mainly through the G(s) class of heterotrimeric G proteins, although they do display some promiscuity in G protein binding. Using cryo-electron microscopy, we determined the structures of the human glucagon receptor (GCGR) bound to glucagon and distinct classes of heterotrimeric G proteins, G(s) or G(i1). These two structures adopt a similar open binding cavity to accommodate G(s) and G(i1). The G(s) binding selectivity of GCGR is explained by a larger interaction interface, but there are specific interactions that affect G(i) more than G(s) binding. Conformational differences in the receptor intracellular loops were found to be key selectivity determinants. These distinctions in transducer engagement were supported by mutagenesis and functional studies.

引用

页码：1346 / +

页数：40

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