Hot topics: Cannabinoid receptor stuctures

Two new reports cover further aspects of cannabinoid receptor binding as defined using cryo-EM. These expand on previous reports of the structure of the human CB₁ cannabinoid receptor with the antagonists taranabant and  AM6538 bound, and with the agonists MDMB-FUBINACA, AM11542 and AM841 bound. Previously reported also is the structure of the CB₂ cannabinoid receptor with the antagonist AM10257 bound.

In the first report (1), a non-selective, high potency agonist WIN55212-2 was bound to a complex of the CB₂ cannabinoid receptor with G_i to “complete the set” of agonist- and antagonist-bound versions of CB₁ and CB₂ receptors. The authors suggest marked similarities in the binding configuration of the agonist WIN55212-2 and the antagonist AM10257. Based on these structures, two novel ligands were generated; one predicted to be an agonist and the other an antagonist. The functional data supported these predictions, although both novel compounds were markedly less potent than their respective positive controls.

In the second report (2), agonist-bound versions of both CB₁ and CB₂ cannabinoid receptors complexed with Gi were also described to ‘complete and expand the set’. AM12033 is a novel nitrilodimethylheptyl analogue of THC with high affinity at both receptors. Structures using this compound were compared to CB₁ receptors bound to the THC-like AM841. The authors suggest similar modes of interaction for agonists at the two receptors, supported by numerous examples of non-selective high potency agonists.

Modelling of the second intracellular loop in both reports suggested a structural basis for the CB₂ receptor to couple poorly to Gs. Indeed, a single amino acid variation (L222 in CB₁ and P139 in CB₂ receptors) was highlighted in both studies and evidenced in the previous literature (https://www.ncbi.nlm.nih.gov/pubmed/23667597).

Comments by Prof. Steve Alexander (@mqzspa), University of Nottingham, UK

(1) Xing C. et al. Cryo-EM Structure of the Human Cannabinoid Receptor CB2-G _i Signaling Complex. Cell (2020) doi:10.1016/j.cell.2020.01.007 [PMID:32004460]

(2) Hua T. et al. Activation and Signaling Mechanism Revealed by Cannabinoid Receptor-G_i Complex Structures. Cell  (2020) doi:10.1016/j.cell.2020.01.008 [PMID:32004463]