Crystal structures of agonist-bound human cannabinoid receptor CB1

Article

关键词: MEMBRANE-PROTEINS;    ACCURATE DOCKING;    GLIDE;    CHEMISTRY;   

DOI  :  10.1038/nature23272

来源: SCIE

【 摘 要 】

The cannabinoid receptor 1 (CB1) is the principal target of the psychoactive constituent of marijuana, the partial agonist Delta(9)-tetrahydrocannabinol (Delta(9)-THC)(1). Here we report two agonist-bound crystal structures of human CB1 in complex with a tetrahydrocannabinol (AM11542) and a hexahydrocannabinol (AM841) at 2.80 angstrom and 2.95 angstrom resolution, respectively. The two CB1-agonist complexes reveal important conformational changes in the overall structure, relative to the antagonist-bound state(2), including a 53% reduction in the volume of the ligand-binding pocket and an increase in the surface area of the G-protein-binding region. In addition, a 'twin toggle switch' of Phe200(3.36) and Trp356(6.48) (superscripts denote Ballesteros-Weinstein numbering(3)) is experimentally observed and appears to be essential for receptor activation. The structures reveal important insights into the activation mechanism of CB1 and provide a molecular basis for predicting the binding modes of Delta(9)-THC, and endogenous and synthetic cannabinoids. The plasticity of the binding pocket of CB1 seems to be a common feature among certain class A G-protein-coupled receptors. These findings should inspire the design of chemically diverse ligands with distinct pharmacological properties.

【 授权许可】

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