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Crystal Structure of the Human Cannabinoid Receptor CB1.
Hua, Tian; Vemuri, Kiran; Pu, Mengchen; Qu, Lu; Han, Gye Won; Wu, Yiran; Zhao, Suwen; Shui, Wenqing; Li, Shanshan; Korde, Anisha; Laprairie, Robert B; Stahl, Edward L; Ho, Jo-Hao; Zvonok, Nikolai; Zhou, Han; Kufareva, Irina; Wu, Beili; Zhao, Qiang; Hanson, Michael A; Bohn, Laura M; Makriyannis, Alexandros; Stevens, Raymond C; Liu, Zhi-Jie.
  • Hua T; iHuman Institute, ShanghaiTech University, Shanghai 201210, China; National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
  • Vemuri K; Center for Drug Discovery, Department of Pharmaceutical Sciences and Department of Chemistry and Chemical Biology, Northeastern University, Boston, MA 02115, USA.
  • Pu M; National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
  • Qu L; iHuman Institute, ShanghaiTech University, Shanghai 201210, China; National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
  • Han GW; Departments of Biological Sciences and Chemistry, Bridge Institute, University of Southern California, Los Angeles, CA 90089, USA.
  • Wu Y; iHuman Institute, ShanghaiTech University, Shanghai 201210, China.
  • Zhao S; iHuman Institute, ShanghaiTech University, Shanghai 201210, China.
  • Shui W; iHuman Institute, ShanghaiTech University, Shanghai 201210, China.
  • Li S; iHuman Institute, ShanghaiTech University, Shanghai 201210, China.
  • Korde A; Center for Drug Discovery, Department of Pharmaceutical Sciences and Department of Chemistry and Chemical Biology, Northeastern University, Boston, MA 02115, USA.
  • Laprairie RB; Departments of Molecular Therapeutics and Neuroscience, The Scripps Research Institute, Jupiter, FL 33458, USA.
  • Stahl EL; Departments of Molecular Therapeutics and Neuroscience, The Scripps Research Institute, Jupiter, FL 33458, USA.
  • Ho JH; Departments of Molecular Therapeutics and Neuroscience, The Scripps Research Institute, Jupiter, FL 33458, USA.
  • Zvonok N; Center for Drug Discovery, Department of Pharmaceutical Sciences and Department of Chemistry and Chemical Biology, Northeastern University, Boston, MA 02115, USA.
  • Zhou H; Center for Drug Discovery, Department of Pharmaceutical Sciences and Department of Chemistry and Chemical Biology, Northeastern University, Boston, MA 02115, USA.
  • Kufareva I; University of California, San Diego, La Jolla, CA 92093, USA.
  • Wu B; CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • Zhao Q; CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • Hanson MA; GPCR Consortium, San Marcos, CA 92078, USA.
  • Bohn LM; Departments of Molecular Therapeutics and Neuroscience, The Scripps Research Institute, Jupiter, FL 33458, USA. Electronic address: lbohn@scripps.edu.
  • Makriyannis A; 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.
  • Stevens RC; 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.
  • Liu ZJ; 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.
Cell ; 167(3): 750-762.e14, 2016 Oct 20.
Article en En | MEDLINE | ID: mdl-27768894
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. CB1 is 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 CB1 in 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 CB1 ligands, such as THC, and synthetic cannabinoids. This enhances our understanding of the molecular basis for the physiological functions of CB1 and provides new opportunities for the design of next-generation CB1-targeting pharmaceuticals.
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Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Pirazoles / Morfolinas / Receptor Cannabinoide CB1 / Antagonistas de Receptores de Cannabinoides Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Año: 2016 Tipo del documento: Article
Texto completo
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Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Pirazoles / Morfolinas / Receptor Cannabinoide CB1 / Antagonistas de Receptores de Cannabinoides Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Año: 2016 Tipo del documento: Article