Crystal Structure of the Human Cannabinoid Receptor CB2

作     者：Li, Xiaoting Hua, Tian Vemuri, Kiran Ho, Jo-Hao Wu, Yiran Wu, Lijie Popov, Petr Benchama, Othman Zvonok, Nikolai Locke, K'ara Qu, Lu Han, Gye Won Iyer, Malliga R. Cinar, Resat Coffey, Nathan J. Wang, Jingjing Wu, Meng Katritch, Vsevolod Zhao, Suwen Kunos, George Bohn, Laura M. Makriyannis, Alexandros Stevens, Raymond C. Liu, Zhi-Jie 

作者机构：ShanghaiTech Univ iHuman Inst Shanghai 201210 Peoples R China ShanghaiTech Univ Sch Life Sci & Technol Shanghai 201210 Peoples R China Chinese Acad Sci Shanghai Inst Biol Sci Inst Biochem & Cell Biol Shanghai Peoples R China Univ Chinese Acad Sci Beijing 100049 Peoples R China Northeastern Univ Dept Chem & Chem Biol Ctr Drug Discovery Boston MA 02115 USA Northeastern Univ Dept Pharmaceut Sci Boston MA 02115 USA Scripps Res Dept Mol Med Jupiter FL 33458 USA Univ Southern Calif Bridge Inst Dept Biol Sci Los Angeles CA 90089 USA NIAAA Lab Physiol Studies NIH Bethesda MD 20892 USA Moscow Inst Phys & Technol Dolgoprudnyi Russia Skolkovo Inst Sci & Technol Moscow Russia 

出 版 物：《CELL》 (细胞)

年 卷 期：2019年第176卷第3期

页      面：459-+页

核心收录：

学科分类：0710[理学-生物学] 07[理学] 09[农学] 

基　　金：National Natural Science Foundation of China [31870744, 31330019] Ministry of Science and Technology of China [2015CB910104] Key R&D Program of China [2016YCF0905902] NIH [R01DA045020, R01DA041435, P01DA009158] National Institute on Alcohol Abuse and Alcoholism, NIH NSF Russian Science Foundation (RSF) [18-74-00117] Shanghai Municipal Government ShanghaiTech University Russian Science Foundation [18-74-00117] Funding Source: Russian Science Foundation 

主　　题：G-protein coupled receptor cannabinoid receptor CB2 crystal structure ligand design subtype selectivity 

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.