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Crystal Structure of the Human Cannabinoid Receptor CB2 | |
Li, Xiaoting1,2,3,4 ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() | |
2019-01-24 | |
Source Publication | CELL
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ISSN | 0092-8674 |
Volume | 176Issue:3Pages:459-+ |
Status | 已发表 |
DOI | 10.1016/j.cell.2018.12.011 |
Abstract | The 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 By | SCI ; SCIE |
Language | 英语 |
Funding Project | Russian Science Foundation (RSF)[18-74-00117] |
WOS Research Area | Biochemistry & Molecular Biology ; Cell Biology |
WOS Subject | Biochemistry & Molecular Biology ; Cell Biology |
WOS ID | WOS:000456526100008 |
Publisher | CELL PRESS |
WOS Keyword | GENERAL FORCE-FIELD ; SELECTIVE ANTAGONIST ; MEMBRANE-PROTEINS ; ACCURATE DOCKING ; BINDING MOTIF ; POTENT ; GLIDE ; STRATEGY ; LIGANDS ; SYSTEM |
Original Document Type | Article |
Citation statistics | |
Document Type | 期刊论文 |
Identifier | https://kms.shanghaitech.edu.cn/handle/2MSLDSTB/30193 |
Collection | iHuman研究所_PI研究组_刘志杰组 iHuman研究所 iHuman研究所_特聘教授组_Raymond Stevens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 iHuman研究所_PI研究组_华甜组 |
Corresponding Author | Liu, Zhi-Jie |
Affiliation | 1.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 Affilication | iHuman Institute; School of Life Science and Technology |
Corresponding Author Affilication | iHuman Institute; School of Life Science and Technology |
First Signature Affilication | iHuman 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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