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Crystal Structure of the Human Cannabinoid Receptor CB2

DOI: 10.1016/j.cell.2018.12.011 DOI Help

Authors: Xiaoting Li (ShanghaiTech University; Shanghai Institutes for Biological Science, Chinese Academy of Sciences; University of the Chinese Academy of Sciences) , Tian Hua (ShanghaiTech University) , Kiran Vemuri (Northeastern University) , Jo-hao Ho (Scripps Research) , Yiran Wu (ShanghaiTech University) , Lijie Wu (ShanghaiTech University) , Petr Popov (University of Southern California; Moscow Institute of Physics and Technology) , Othman Benchama (Northeastern University) , Nikolai Zvonok (Northeastern University) , K’ara Locke (Scripps Research) , Lu Qu (ShanghaiTech University) , Gye Won Han (University of Southern California) , Malliga R. Iyer (National Institute on Alcohol Abuse and Alcoholism, NIH) , Resat Cinar (National Institute on Alcohol Abuse and Alcoholism, NIH) , Nathan J. Coffey (National Institute on Alcohol Abuse and Alcoholism, NIH) , Jingjing Wang (ShanghaiTech University; Shanghai Institutes for Biological Science, Chinese Academy of Sciences; University of the Chinese Academy of Sciences) , Meng Wu (ShanghaiTech University; University of the Chinese Academy of Sciences) , Vsevolod Katritch (University of Southern California; Moscow Institute of Physics and Technology, Dolgoprudny) , Suwen Zhao (ShanghaiTech University) , George Kunos (National Institute on Alcohol Abuse and Alcoholism, NIH) , Laura M. Bohn (Scripps Research) , Alexandros Makriyannis (Northeastern University; Northeastern University) , Raymond C. Stevens (ShanghaiTech University; University of Southern California) , Zhi-jie Liu (ShanghaiTech University)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Cell

State: Published (Approved)
Published: January 2019

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 Å 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.

Journal Keywords: G-protein coupled receptor; cannabinoid receptor CB2; crystal structure; ligand design; subtype selectivity

Subject Areas: Biology and Bio-materials, Medicine


Instruments: I24-Microfocus Macromolecular Crystallography

Other Facilities: Spring-8; Swiss Light Source