Cryo-EM Structure of the Human Cannabinoid Receptor CB2-G(i) Signaling Complex

doi:10.1016/j.cell.2020.01.007

	Cryo-EM Structure of the Human Cannabinoid Receptor CB2-G(i) Signaling Complex
	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
刊名	CELL
	2020-02-20
卷号	180 期号:4 页码:645-+
ISSN号	0092-8674
DOI	10.1016/j.cell.2020.01.007
通讯作者	Zhang, Cheng(chengzh@pitt.edu) ; Xu, H. Eric(eric.xu@simm.ac.cn) ; Xie, Xiang-Qun(xix15@pitt.edu)
英文摘要	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.
资助项目	National Institutes of Health (NIH) National Institute on Drug Abuse (NIDA)[P30 DA035778A1] ; NIH[R01 DA025612] ; NIH[1R35GM128641] ; NIH[1R01GM127710] ; Jay and Betty Van Andel Foundation ; Ministry of Science and Technology of China[XDB08020303] ; UCAS Joint PhD Training Program
WOS关键词	MOLECULAR-DYNAMICS SIMULATION ; CB1R INVERSE AGONIST ; CB2 RECEPTOR ; OVERWEIGHT PATIENTS ; CRYSTAL-STRUCTURE ; EXPRESSION ; ACCURACY ; OPTIMIZATION ; TARANABANT ; PREDICTION
WOS研究方向	Biochemistry & Molecular Biology ; Cell Biology
语种	英语
出版者	CELL PRESS
WOS记录号	WOS:000514846600004
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/281535]
专题	中国科学院上海药物研究所
通讯作者	Zhang, Cheng; Xu, H. Eric; Xie, Xiang-Qun
作者单位	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
推荐引用方式 GB/T 7714	Xing, Changrui,Zhuang, Youwen,Xu, Ting-Hai,et al. Cryo-EM Structure of the Human Cannabinoid Receptor CB2-G(i) Signaling Complex[J]. CELL,2020,180(4):645-+.
APA	Xing, Changrui.,Zhuang, Youwen.,Xu, Ting-Hai.,Feng, Zhiwei.,Zhou, X. Edward.,...&Xie, Xiang-Qun.(2020).Cryo-EM Structure of the Human Cannabinoid Receptor CB2-G(i) Signaling Complex.CELL,180(4),645-+.
MLA	Xing, Changrui,et al."Cryo-EM Structure of the Human Cannabinoid Receptor CB2-G(i) Signaling Complex".CELL 180.4(2020):645-+.