The cannabinoid receptor 1 (CB 1 ) is the principal target of the psychoactive constituent of marijuana, the partial agonist Δ 9 -tetrahydrocannabinol (Δ 9 -THC). Here we report two agonist-bound crystal structures of human CB 1 in complex with a tetrahydrocannabinol (AM11542) and a hexahydrocannabinol (AM841) at 2.80 Å and 2.95 Å resolution, respectively. The two CB 1 -agonist complexes reveal important conformational changes in the overall structure, relative to the antagonist-bound state, 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) is experimentally observed and appears to be essential for receptor activation. The structures reveal important insights into the activation mechanism of CB 1 and provide a molecular basis for predicting the binding modes of Δ 9 -THC, and endogenous and synthetic cannabinoids. The plasticity of the binding pocket of CB 1 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.
