Activation and Signaling Mechanism Revealed by Cannabinoid Receptor-G(i) Complex Structures
Hua, Tian1; Li, Xiaoting1; Wu, Lijie1; Iliopoulos-Tsoutsouvas, Christos2,3; Wang, Yuxia1; Wu, Meng1,4; Shen, Ling1,4; Johnston, Christina A.5,6; Nikas, Spyros P.2,3; Song, Feng7; Song, Xiyong8; Yuan, Shuguang9; Sun, Qianqian1; Wu, Yiran1; Jiang, Shan2,3; Grim, Travis W.5,6; Benchama, Othman2,3; Stahl, Edward L.5,6; Zvonok, Nikolai2,3; Zhao, Suwen1,4; Bohn, Laura M.5,6; Makriyannis, Alexandros2,10,11; Liu, Zhi-Jie1,4,8
2020-02-20
Source PublicationCELL
ISSN0092-8674
Volume180Issue:4Pages:655-+
Status已发表
DOI10.1016/j.cell.2020.01.008
AbstractHuman endocannabinoid systems modulate multiple physiological processes mainly through the activation of cannabinoid receptors CB1 and CB2. Their high sequence similarity, low agonist selectivity, and lack of activation and G protein-coupling knowledge have hindered the development of therapeutic applications. Importantly, missing structural information has significantly held back the development of promising CB2-selective agonist drugs for treating inflammatory and neuropathic pain without the psychoactivity of CB1. Here, we report the cryoelectron microscopy structures of synthetic cannabinoid-bound CB2 and CB1 in complex with G(i), as well as agonist-bound CB2 crystal structure. Of important scientific and therapeutic benefit, our results reveal a diverse activation and signaling mechanism, the structural basis of CB2-selective agonists design, and the unexpected interaction of cholesterol with CB1, suggestive of its endogenous allosteric modulating role.
Indexed BySCI
Language英语
Funding ProjectNIH[R01DA045020] ; NIH[R01DA041435] ; NIH[P01DA009158]
WOS Research AreaBiochemistry & Molecular Biology ; Cell Biology
WOS SubjectBiochemistry & Molecular Biology ; Cell Biology
WOS IDWOS:000514846600005
PublisherCELL PRESS
EISSN1097-4172
WOS KeywordMOLECULAR-DYNAMICS ; MEMBRANE-PROTEINS ; CRYSTAL-STRUCTURE ; CB1 ; AGONIST ; SYSTEM ; INTEGRATION ; STRATEGY ; DOCKING ; MOTION
Original Document TypeArticle
Citation statistics
Cited Times:1[WOS]   [WOS Record]     [Related Records in WOS]
Document Type期刊论文
Identifierhttp://kms.shanghaitech.edu.cn/handle/2MSLDSTB/114838
CollectioniHuman研究所_PI研究组_刘志杰组
iHuman研究所_公共科研平台_生命科学电镜平台
iHuman研究所_PI研究组_赵素文组
iHuman研究所_科学装置(X)_膜蛋白同步辐射线站
生命科学与技术学院_硕士生
生命科学与技术学院_博士生
iHuman研究所_PI研究组_华甜组
Corresponding AuthorHua, Tian; Liu, Zhi-Jie
Affiliation1.ShanghaiTech Univ, iHuman Inst, Shanghai 201210, Peoples R China
2.Northeastern Univ, Ctr Drug Discovery, Boston, MA 02115 USA
3.Northeastern Univ, Dept Pharmaceut Sci, Boston, MA 02115 USA
4.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai 201210, Peoples R China
5.Scripps Res, Dept Mol Med, Jupiter, FL 33458 USA
6.Scripps Res, Dept Neurosci, Jupiter, FL 33458 USA
7.Dezhou Univ, Sch Life Sci, Dezhou 253023, Shandong, Peoples R China
8.Kunming Med Univ, Inst Mol & Clin Med, Kunming 650500, Yunnan, Peoples R China
9.Chinese Acad Sci, Shenzhen Inst Adv Technol, Res Ctr Comp Aided Drug Discovery, Shenzhen 518055, Peoples R China
10.Northeastern Univ, Dept Chem, Boston, MA 02115 USA
11.Northeastern Univ, Dept Biol Chem, Boston, MA 02115 USA
First Author AffilicationiHuman Institute
Corresponding Author AffilicationiHuman Institute;  School of Life Science and Technology
First Signature AffilicationiHuman Institute
Recommended Citation
GB/T 7714
Hua, Tian,Li, Xiaoting,Wu, Lijie,et al. Activation and Signaling Mechanism Revealed by Cannabinoid Receptor-G(i) Complex Structures[J]. CELL,2020,180(4):655-+.
APA Hua, Tian.,Li, Xiaoting.,Wu, Lijie.,Iliopoulos-Tsoutsouvas, Christos.,Wang, Yuxia.,...&Liu, Zhi-Jie.(2020).Activation and Signaling Mechanism Revealed by Cannabinoid Receptor-G(i) Complex Structures.CELL,180(4),655-+.
MLA Hua, Tian,et al."Activation and Signaling Mechanism Revealed by Cannabinoid Receptor-G(i) Complex Structures".CELL 180.4(2020):655-+.
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