Structural basis of THC analog activity at the Cannabinoid 1 receptor.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 39779700.
- Also identified by DOI 10.1038/s41467-024-55808-4 and PMC identifier 11711184.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
Abstract
Tetrahydrocannabinol (THC) is the principal psychoactive compound derived from the cannabis plant Cannabis sativa and approved for emetic conditions, appetite stimulation and sleep apnea relief. THC's psychoactive actions are mediated primarily by the cannabinoid receptor CB<sub>1</sub>. Here, we determine the cryo-EM structure of HU210, a THC analog and widely used tool compound, bound to CB<sub>1</sub> and its primary transducer, G<sub>i1</sub>. We leverage this structure for docking and 1000 ns molecular dynamics simulations of THC and 10 structural analogs delineating their spatiotemporal interactions at the molecular level. Furthermore, we pharmacologically profile their recruitment of G<sub>i</sub> and β-arrestins and reversibility of binding from an active complex. By combining detailed CB<sub>1</sub> structural information with molecular models and signaling data we uncover the differential spatiotemporal interactions these ligands make to receptors governing potency, efficacy, bias and kinetics. This may help explain the actions of abused substances, advance fundamental receptor activation studies and design better medicines.
Medical subject headings
- Dronabinol
- Receptor, Cannabinoid, CB1
- Molecular Dynamics Simulation
- Cryoelectron Microscopy