title: Crystal Structure of the Human Cannabinoid Receptor CB1.
abstract: Cannabinoid receptor 1 (CB1) is the principal target of Δ9-tetrahydrocannabinol (THC), a psychoactive chemical from Cannabis sativa with a wide range of therapeutic applications and a long history of recreational use. CB1is activated by endocannabinoids and is a promising therapeutic target for pain management, inflammation, obesity, and substance abuse disorders. Here, we present the 2.8 Å crystal structure of human CB1in complex with AM6538, a stabilizing antagonist, synthesized and characterized for this structural study. The structure of the CB1-AM6538 complex reveals key features of the receptor and critical interactions for antagonist binding. In combination with functional studies and molecular modeling, the structure provides insight into the binding mode of naturally occurring CB1ligands, such as THC, and synthetic cannabinoids. This enhances our understanding of the molecular basis for the physiological functions of CB1and provides new opportunities for the design of next-generation CB1-targeting pharmaceuticals.
authors: iHuman Institute, ShanghaiTech University, Shanghai 201210, China; National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
authors: Tian
authors: T
authors: Hua
authors: Center for Drug Discovery, Department of Pharmaceutical Sciences and Department of Chemistry and Chemical Biology, Northeastern University, Boston, MA 02115, USA.
authors: Kiran
authors: K
authors: Vemuri
authors: National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
authors: Mengchen
authors: M
authors: Pu
authors: iHuman Institute, ShanghaiTech University, Shanghai 201210, China; National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
authors: Lu
authors: L
authors: Qu
authors: Departments of Biological Sciences and Chemistry, Bridge Institute, University of Southern California, Los Angeles, CA 90089, USA.
authors: Gye Won
authors: GW
authors: Han
authors: iHuman Institute, ShanghaiTech University, Shanghai 201210, China.
authors: Yiran
authors: Y
authors: Wu
authors: iHuman Institute, ShanghaiTech University, Shanghai 201210, China.
authors: Suwen
authors: S
authors: Zhao
authors: iHuman Institute, ShanghaiTech University, Shanghai 201210, China.
authors: Wenqing
authors: W
authors: Shui
authors: iHuman Institute, ShanghaiTech University, Shanghai 201210, China.
authors: Shanshan
authors: S
authors: Li
authors: Center for Drug Discovery, Department of Pharmaceutical Sciences and Department of Chemistry and Chemical Biology, Northeastern University, Boston, MA 02115, USA.
authors: Anisha
authors: A
authors: Korde
authors: Departments of Molecular Therapeutics and Neuroscience, The Scripps Research Institute, Jupiter, FL 33458, USA.
authors: Robert B
authors: RB
authors: Laprairie
authors: Departments of Molecular Therapeutics and Neuroscience, The Scripps Research Institute, Jupiter, FL 33458, USA.
authors: Edward L
authors: EL
authors: Stahl
authors: Departments of Molecular Therapeutics and Neuroscience, The Scripps Research Institute, Jupiter, FL 33458, USA.
authors: Jo-Hao
authors: JH
authors: Ho
authors: Center for Drug Discovery, Department of Pharmaceutical Sciences and Department of Chemistry and Chemical Biology, Northeastern University, Boston, MA 02115, USA.
authors: Nikolai
authors: N
authors: Zvonok
authors: Center for Drug Discovery, Department of Pharmaceutical Sciences and Department of Chemistry and Chemical Biology, Northeastern University, Boston, MA 02115, USA.
authors: Han
authors: H
authors: Zhou
authors: University of California, San Diego, La Jolla, CA 92093, USA.
authors: Irina
authors: I
authors: Kufareva
authors: CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors: Beili
authors: B
authors: Wu
authors: CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors: Qiang
authors: Q
authors: Zhao
authors: GPCR Consortium, San Marcos, CA 92078, USA.
authors: Michael A
authors: MA
authors: Hanson
authors: Departments of Molecular Therapeutics and Neuroscience, The Scripps Research Institute, Jupiter, FL 33458, USA. Electronic address: lbohn@scripps.edu.
authors: Laura M
authors: LM
authors: Bohn
authors: Center for Drug Discovery, Department of Pharmaceutical Sciences and Department of Chemistry and Chemical Biology, Northeastern University, Boston, MA 02115, USA. Electronic address: a.makriyannis@northeastern.edu.
authors: Alexandros
authors: A
authors: Makriyannis
authors: iHuman Institute, ShanghaiTech University, Shanghai 201210, China; Departments of Biological Sciences and Chemistry, Bridge Institute, University of Southern California, Los Angeles, CA 90089, USA. Electronic address: stevens@shanghaitech.edu.cn.
authors: Raymond C
authors: RC
authors: Stevens
authors: iHuman Institute, ShanghaiTech University, Shanghai 201210, China; National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China. Electronic address: liuzhj@shanghaitech.edu.cn.
authors: Zhi-Jie
authors: ZJ
authors: Liu
mesh_terms: D001665:Binding Sites; D063387:Cannabinoid Receptor Antagonists / Q000737:chemistry*; D002186:Cannabinoids / Q000494:pharmacology; D002188:Cannabis / Q000737:chemistry; D018360:Crystallography, X-Ray; D013759:Dronabinol / Q000494:pharmacology; D063388:Endocannabinoids / Q000494:pharmacology; D006801:Humans; D008024:Ligands; D009025:Morpholines / Q000138:chemical synthesis / Q000737:chemistry*; D011485:Protein Binding; D000072756:Protein Conformation, alpha-Helical; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry*; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors* / Q000737:chemistry*
chemical_list: C551825:AM6545; D063387:Cannabinoid Receptor Antagonists; D002186:Cannabinoids; D063388:Endocannabinoids; D008024:Ligands; D009025:Morpholines; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; D013759:Dronabinol
keywords: AM6538; G protein-coupled receptor; THC; cannabinoid receptor CB1; cell signalling; crystal structure; marijuana; rimonabant; stabilizing antagonist