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
2019-01-24
发表期刊CELL
ISSN0092-8674
卷号176期号:3页码:459-+
发表状态已发表
DOI10.1016/j.cell.2018.12.011
摘要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.
收录类别SCI ; SCIE
语种英语
资助项目Russian Science Foundation (RSF)[18-74-00117]
WOS研究方向Biochemistry & Molecular Biology ; Cell Biology
WOS类目Biochemistry & Molecular Biology ; Cell Biology
WOS记录号WOS:000456526100008
出版者CELL PRESS
WOS关键词GENERAL FORCE-FIELD ; SELECTIVE ANTAGONIST ; MEMBRANE-PROTEINS ; ACCURATE DOCKING ; BINDING MOTIF ; POTENT ; GLIDE ; STRATEGY ; LIGANDS ; SYSTEM
原始文献类型Article
引用统计
文献类型期刊论文
条目标识符https://kms.shanghaitech.edu.cn/handle/2MSLDSTB/30193
专题iHuman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
iHuman研究所_PI研究组_华甜组
通讯作者Liu, Zhi-Jie
作者单位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
第一作者单位iHuman研究所;  生命科学与技术学院
通讯作者单位iHuman研究所;  生命科学与技术学院
第一作者的第一单位iHuman研究所
推荐引用方式
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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