Your browser doesn't support javascript.
loading
Crystal Structure of the Human Cannabinoid Receptor CB2.
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.
Afiliação
  • Li X; iHuman Institute, ShanghaiTech University, Shanghai 201210, China; School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China; Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Science, Chinese Academy of Sciences, Shanghai, China; University
  • Hua T; iHuman Institute, ShanghaiTech University, Shanghai 201210, China.
  • Vemuri K; Center for Drug Discovery, Department of Chemistry and Chemical Biology, Northeastern University, Boston, MA 02115, USA; Department of Pharmaceutical Sciences, Northeastern University, Boston, MA 02115, USA.
  • Ho JH; Department of Molecular Medicine, Scripps Research, Jupiter, FL 33458, USA.
  • Wu Y; iHuman Institute, ShanghaiTech University, Shanghai 201210, China.
  • Wu L; iHuman Institute, ShanghaiTech University, Shanghai 201210, China.
  • Popov P; Department of Biological Sciences, Bridge Institute, University of Southern California, Los Angeles, CA 90089, USA; Moscow Institute of Physics and Technology, Dolgoprudny, Russia.
  • Benchama O; Center for Drug Discovery, Department of Chemistry and Chemical Biology, Northeastern University, Boston, MA 02115, USA; Department of Pharmaceutical Sciences, Northeastern University, Boston, MA 02115, USA.
  • Zvonok N; Center for Drug Discovery, Department of Chemistry and Chemical Biology, Northeastern University, Boston, MA 02115, USA; Department of Pharmaceutical Sciences, Northeastern University, Boston, MA 02115, USA.
  • Locke K; Department of Molecular Medicine, Scripps Research, Jupiter, FL 33458, USA.
  • Qu L; iHuman Institute, ShanghaiTech University, Shanghai 201210, China.
  • Han GW; Department of Biological Sciences, Bridge Institute, University of Southern California, Los Angeles, CA 90089, USA.
  • Iyer MR; Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, MD 20892, USA.
  • Cinar R; Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, MD 20892, USA.
  • Coffey NJ; Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, MD 20892, USA.
  • Wang J; iHuman Institute, ShanghaiTech University, Shanghai 201210, China; School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China; Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Science, Chinese Academy of Sciences, Shanghai, China; University
  • Wu M; iHuman Institute, ShanghaiTech University, Shanghai 201210, China; School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China; University of the Chinese Academy of Sciences, Beijing 100049, China.
  • Katritch V; Department of Biological Sciences, Bridge Institute, University of Southern California, Los Angeles, CA 90089, USA; Moscow Institute of Physics and Technology, Dolgoprudny, Russia.
  • Zhao S; iHuman Institute, ShanghaiTech University, Shanghai 201210, China; School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China.
  • Kunos G; Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, MD 20892, USA.
  • Bohn LM; Department of Molecular Medicine, Scripps Research, Jupiter, FL 33458, USA.
  • Makriyannis A; Center for Drug Discovery, Department of Chemistry and Chemical Biology, Northeastern University, Boston, MA 02115, USA; Department of Pharmaceutical Sciences, Northeastern University, Boston, MA 02115, USA.
  • Stevens RC; iHuman Institute, ShanghaiTech University, Shanghai 201210, China; School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China; Department of Biological Sciences, Bridge Institute, University of Southern California, Los Angeles, CA 90089, USA.
  • Liu ZJ; iHuman Institute, ShanghaiTech University, Shanghai 201210, China; School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China. Electronic address: liuzhj@shanghaitech.edu.cn.
Cell ; 176(3): 459-467.e13, 2019 01 24.
Article em En | MEDLINE | ID: mdl-30639103
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.
Assuntos
Palavras-chave
Texto completo
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Receptor CB2 de Canabinoide Tipo de estudo: Prognostic_studies Limite: Animals / Humans Idioma: En Revista: Cell Ano de publicação: 2019 Tipo de documento: Article
Texto completo
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Receptor CB2 de Canabinoide Tipo de estudo: Prognostic_studies Limite: Animals / Humans Idioma: En Revista: Cell Ano de publicação: 2019 Tipo de documento: Article