Cryo-EM Structure of the Human Cannabinoid Receptor CB2-Gi Signaling Complex

被引：183

作者：

Xing, Changrui ^{[1
,2
,3
,4
,5
]}

Zhuang, Youwen ^{[6
,7
,8
]}

Xu, Ting-Hai ^{[8
]}

Feng, Zhiwei ^{[1
,2
,3
,4
,5
]}

Zhou, X. Edward ^{[8
]}

Chen, Maozi ^{[1
,2
]}

Wang, Lei ^{[9
]}

Meng, Xing ^{[10
]}

Xue, Ying ^{[1
,2
,11
]}

Wang, Junmei ^{[1
,2
]}

Liu, Heng ^{[9
]}

McGuire, Terence Francis ^{[1
,2
]}

Zhao, Gongpu ^{[10
]}

Melcher, Karsten ^{[8
]}

Zhang, Cheng ^{[9
]}

Xu, H. Eric ^{[6
]}

Xie, Xiang-Qun ^{[1
,2
,3
,4
,5
]}

机构：

[1] Univ Pittsburgh, Sch Pharm, Computat Chem Genom Screen Ctr, Dept Pharmaceut Sci, Pittsburgh, PA 15261 USA

[2] Univ Pittsburgh, NIDA Natl Ctr Excellence Computat Drug Abuse Res, Pittsburgh, PA 15261 USA

[3] Univ Pittsburgh, Drug Discovery Inst, Pittsburgh, PA 15261 USA

[4] Univ Pittsburgh, Dept Computat Biol, Pittsburgh, PA 15261 USA

[5] Univ Pittsburgh, Dept Biol Struct, Pittsburgh, PA 15261 USA

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

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

[8] Van Andel Inst, Program Struct Biol, Ctr Canc & Cell Biol, Grand Rapids, MI 49503 USA

[9] Univ Pittsburgh, Sch Med, Dept Pharmacol & Chem Biol, Lab GPCR Biol, Pittsburgh, PA 15261 USA

[10] Van Andel Res Inst, David Van Andel Adv Cryoelectron Microscopy Suite, Grand Rapids, MI 49503 USA

[11] Univ Pittsburgh, Sch Pharm, Dept Pharm & Therapeut, Pittsburgh, PA 15261 USA

来源：

CELL | 2020年 / 180卷 / 04期

基金：

美国国家卫生研究院;

关键词：

MOLECULAR-DYNAMICS SIMULATION; CB1R INVERSE AGONIST; CB2; RECEPTOR; OVERWEIGHT PATIENTS; CRYSTAL-STRUCTURE; EXPRESSION; ACCURACY; OPTIMIZATION; TARANABANT; PREDICTION;

D O I：

10.1016/j.cell.2020.01.007

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Drugs selectively targeting CB2 hold promise for treating neurodegenerative disorders, inflammation, and pain while avoiding psychotropic side effects mediated by CB1. The mechanisms underlying CB2 activation and signaling are poorly understood but critical for drug design. Here we report the cryo-EM structure of the human CB2-G(i) signaling complex bound to the agonist WIN 55,212-2. The 3D structure reveals the binding mode of WIN 55,212-2 and structural determinants for distinguishing CB2 agonists from antagonists, which are supported by a pair of rationally designed agonist and antagonist. Further structural analyses with computational docking results uncover the differences between CB2 and CB1 in receptor activation, ligand recognition, and G(i) coupling. These findings are expected to facilitate rational structure-based discovery of drugs targeting the cannabinoid system.

引用

页码：645 / +

页数：23

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