Nature 547, 468–471 (27 July 2017)

The cannabinoid receptor 1 (CB₁) is the principal target of the psychoactive constituent of marijuana, the partial agonist Δ⁹-tetrahydrocannabinol (Δ⁹-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 Å and 2.95 Å resolution, respectively. The two CB₁–agonist complexes reveal important conformational changes in the overall structure, relative to the antagonist-bound state², 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 numbering³) is experimentally observed and appears to be essential for receptor activation.