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Activation and Signaling Mechanism Revealed by Cannabinoid Receptor-Gi Complex Structures.
Hua, Tian; Li, Xiaoting; Wu, Lijie; Iliopoulos-Tsoutsouvas, Christos; Wang, Yuxia; Wu, Meng; Shen, Ling; Brust, Christina A; Nikas, Spyros P; Song, Feng; Song, Xiyong; Yuan, Shuguang; Sun, Qianqian; Wu, Yiran; Jiang, Shan; Grim, Travis W; Benchama, Othman; Stahl, Edward L; Zvonok, Nikolai; Zhao, Suwen; Bohn, Laura M; Makriyannis, Alexandros; Liu, Zhi-Jie.
  • Hua T; iHuman Institute, ShanghaiTech University, Shanghai 201210, China. Electronic address: huatian@shanghaitech.edu.cn.
  • Li X; iHuman Institute, ShanghaiTech University, Shanghai 201210, China.
  • Wu L; iHuman Institute, ShanghaiTech University, Shanghai 201210, China.
  • Iliopoulos-Tsoutsouvas C; Center for Drug Discovery and Department of Pharmaceutical Sciences, Northeastern University, Boston, MA 02115, USA.
  • Wang Y; iHuman Institute, ShanghaiTech University, Shanghai 201210, China.
  • Wu M; iHuman Institute, ShanghaiTech University, Shanghai 201210, China; School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China.
  • Shen L; iHuman Institute, ShanghaiTech University, Shanghai 201210, China; School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China.
  • Brust CA; Departments of Molecular Medicine and Neuroscience, Scripps Research, Jupiter, FL 33458, USA.
  • Nikas SP; Center for Drug Discovery and Department of Pharmaceutical Sciences, Northeastern University, Boston, MA 02115, USA.
  • Song F; School of Life Science, Dezhou University, Dezhou 253023, Shandong Province, China.
  • Song X; Institute of Molecular and Clinical Medicine, Kunming Medical University, Kunming 650500, Yunnan Province, China.
  • Yuan S; The Research Center for Computer-aided Drug Discovery, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China.
  • Sun Q; iHuman Institute, ShanghaiTech University, Shanghai 201210, China.
  • Wu Y; iHuman Institute, ShanghaiTech University, Shanghai 201210, China.
  • Jiang S; Center for Drug Discovery and Department of Pharmaceutical Sciences, Northeastern University, Boston, MA 02115, USA.
  • Grim TW; Departments of Molecular Medicine and Neuroscience, Scripps Research, Jupiter, FL 33458, USA.
  • Benchama O; Center for Drug Discovery and Department of Pharmaceutical Sciences, Northeastern University, Boston, MA 02115, USA.
  • Stahl EL; Departments of Molecular Medicine and Neuroscience, Scripps Research, Jupiter, FL 33458, USA.
  • Zvonok N; Center for Drug Discovery and Department of Pharmaceutical Sciences, Northeastern University, Boston, MA 02115, USA.
  • Zhao S; iHuman Institute, ShanghaiTech University, Shanghai 201210, China; School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China.
  • Bohn LM; Departments of Molecular Medicine and Neuroscience, Scripps Research, Jupiter, FL 33458, USA.
  • Makriyannis A; Center for Drug Discovery and Department of Pharmaceutical Sciences, Northeastern University, Boston, MA 02115, USA; Center for Drug Discovery and Departments of Chemistry and Chemical Biology, Northeastern University, Boston, MA 02115, USA.
  • Liu ZJ; iHuman Institute, ShanghaiTech University, Shanghai 201210, China; School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China; Institute of Molecular and Clinical Medicine, Kunming Medical University, Kunming 650500, Yunnan Province, China. Electronic address: liuzhj@shan
Cell ; 180(4): 655-665.e18, 2020 02 20.
Article en En | MEDLINE | ID: mdl-32004463
ABSTRACT
Human endocannabinoid systems modulate multiple physiological processes mainly through the activation of cannabinoid receptors CB1 and CB2. Their high sequence similarity, low agonist selectivity, and lack of activation and G protein-coupling knowledge have hindered the development of therapeutic applications. Importantly, missing structural information has significantly held back the development of promising CB2-selective agonist drugs for treating inflammatory and neuropathic pain without the psychoactivity of CB1. Here, we report the cryoelectron microscopy structures of synthetic cannabinoid-bound CB2 and CB1 in complex with Gi, as well as agonist-bound CB2 crystal structure. Of important scientific and therapeutic benefit, our results reveal a diverse activation and signaling mechanism, the structural basis of CB2-selective agonists design, and the unexpected interaction of cholesterol with CB1, suggestive of its endogenous allosteric modulating role.
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Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Transducción de Señal / Subunidades alfa de la Proteína de Unión al GTP Gi-Go / Receptor Cannabinoide CB1 / Receptor Cannabinoide CB2 / Agonistas de Receptores de Cannabinoides Límite: Animals / Humans Idioma: En Año: 2020 Tipo del documento: Article
Texto completo
Imprimir
XML
PubMed Links
Search on Google

Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Transducción de Señal / Subunidades alfa de la Proteína de Unión al GTP Gi-Go / Receptor Cannabinoide CB1 / Receptor Cannabinoide CB2 / Agonistas de Receptores de Cannabinoides Límite: Animals / Humans Idioma: En Año: 2020 Tipo del documento: Article