Scientists capture crystal structures of cannabinoid receptor in action

Until now, scientists only had crystal structures of the human cannabinoid receptor, CB₁ in its inactive, antagonist-bound form, but a new study has obtained crystal structures of CB₁ in its active state. CB₁ is the primary target of delta-9-tetrahydrocannabinol (THC), the psychoactive compound in cannabis. The findings highlight how cannabinoids trigger their effects and provide a framework for designing new medicines that act more selectively on this drug target.

To capture CB₁ in its active state, Zhi-Jie Liu, of ShanghaiTech University in China, and colleagues engineered a CB₁–flavodoxin fusion protein and crystallised it in a lipidic cubic phase with two synthetic agonists, AM11542 and AM841. These molecules mimic THC’s tricyclic ring system but carry longer alkyl chains and chemical substituents that lock the receptor in its switched-on form.

Relative to the antagonist-bound state, the two structures displayed significant structural rearrangements. The ligand-binding pocket contracts by 53% when bound to AM11542 and AM841, while helices I and II bend inward more than in any other G protein-coupled receptor structure solved to date. On the intracellular side, helix VI swings outward by 8Å, creating space for G-protein binding. Interestingly, a cholesterol molecule appears wedged between helices II, III and IV, a feature not observed in previously reported inactive-state structures. At the molecular level, activation relies on a newly observed ‘twin toggle switch’ – two aromatic residues that flip when agonists bind, providing the trigger for downstream signalling. Comparisons with other GPCRs suggest CB₁ is remarkably flexible, explaining its ability to accommodate chemically diverse ligands.

These insights resolve long-standing structural questions about CB₁ but also give direction to developing safer cannabinoid-based therapies for pain and neurological diseases.