Crystal Structure of the Human Cannabinoid Receptor CB2
Li, Xiaoting1,2,3,4; Hua, Tian1; Vemuri, Kiran5,6; Ho, Jo-Hao7; Wu, Yiran1; Wu, Lijie1; Popov, Petr10,11; Benchama, Othman5,6; Zvonok, Nikolai5,6; Locke, K'ara7; Qu, Lu1; Han, Gye Won8; Iyer, Malliga R.9; Cinar, Resat9; Coffey, Nathan J.9; Wang, Jingjing1,2,3,4; Wu, Meng1,2,4; Katritch, Vsevolod8,10; Zhao, Suwen1,2; Kunos, George9; Bohn, Laura M.7; Makriyannis, Alexandros5,6; Stevens, Raymond C.1,2,8; Liu, Zhi-Jie1,2
2019-01-24
Source PublicationCELL
ISSN0092-8674
Volume176Issue:3Pages:459-+
DOI10.1016/j.cell.2018.12.011
AbstractThe cannabinoid receptor CB2 is predominately expressed in the immune system, and selective modulation of CB2 without the psychoactivity of CB1 has therapeutic potential in inflammatory, fibrotic, and neurodegenerative diseases. Here, we report the crystal structure of human CB2 in complex with a rationally designed antagonist, AM10257, at 2.8 angstrom resolution. The CB2-AM10257 structure reveals a distinctly different binding pose compared with CB1. However, the extracellular portion of the antagonist-bound CB2 shares a high degree of conformational similarity with the agonist-bound CB1, which led to the discovery of AM10257's unexpected opposing functional profile of CB2 antagonism versus CB1 agonism. Further structural analysis using mutagenesis studies and molecular docking revealed the molecular basis of their function and selectivity for CB2 and CB1. Additional analyses of our designed antagonist and agonist pairs provide important insight into the activation mechanism of CB2. The present findings should facilitate rational drug design toward precise modulation of the endocannabinoid system.
Indexed BySCI
Language英语
Funding ProjectRussian Science Foundation (RSF)[18-74-00117]
WOS Research AreaBiochemistry & Molecular Biology ; Cell Biology
WOS SubjectBiochemistry & Molecular Biology ; Cell Biology
WOS IDWOS:000456526100008
PublisherCELL PRESS
WOS KeywordGENERAL FORCE-FIELD ; SELECTIVE ANTAGONIST ; MEMBRANE-PROTEINS ; ACCURATE DOCKING ; BINDING MOTIF ; POTENT ; GLIDE ; STRATEGY ; LIGANDS ; SYSTEM
Original Document TypeArticle
Citation statistics
Cited Times:16[WOS]   [WOS Record]     [Related Records in WOS]
Document Type期刊论文
Identifierhttp://kms.shanghaitech.edu.cn/handle/2MSLDSTB/30193
CollectioniHuman研究所
iHuman研究所_特聘教授组_Raymond Stevens组
iHuman研究所_PI研究组_刘志杰组
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_博士生
Corresponding AuthorLiu, Zhi-Jie
Affiliation1.ShanghaiTech Univ, iHuman Inst, Shanghai 201210, Peoples R China
2.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai 201210, Peoples R China
3.Chinese Acad Sci, Shanghai Inst Biol Sci, Inst Biochem & Cell Biol, Shanghai, Peoples R China
4.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
5.Northeastern Univ, Dept Chem & Chem Biol, Ctr Drug Discovery, Boston, MA 02115 USA
6.Northeastern Univ, Dept Pharmaceut Sci, Boston, MA 02115 USA
7.Scripps Res, Dept Mol Med, Jupiter, FL 33458 USA
8.Univ Southern Calif, Bridge Inst, Dept Biol Sci, Los Angeles, CA 90089 USA
9.NIAAA, Lab Physiol Studies, NIH, Bethesda, MD 20892 USA
10.Moscow Inst Phys & Technol, Dolgoprudnyi, Russia
11.Skolkovo Inst Sci & Technol, Moscow, Russia
First Author AffilicationiHuman Institute;  School of Life Science and Technology
Corresponding Author AffilicationiHuman Institute;  School of Life Science and Technology
First Signature AffilicationiHuman Institute
Recommended Citation
GB/T 7714
Li, Xiaoting,Hua, Tian,Vemuri, Kiran,et al. Crystal Structure of the Human Cannabinoid Receptor CB2[J]. CELL,2019,176(3):459-+.
APA Li, Xiaoting.,Hua, Tian.,Vemuri, Kiran.,Ho, Jo-Hao.,Wu, Yiran.,...&Liu, Zhi-Jie.(2019).Crystal Structure of the Human Cannabinoid Receptor CB2.CELL,176(3),459-+.
MLA Li, Xiaoting,et al."Crystal Structure of the Human Cannabinoid Receptor CB2".CELL 176.3(2019):459-+.
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