A Single Point Mutation Blocks the Entrance of Ligands to the Cannabinoid CB₂ Receptor via the Lipid Bilayer.

ABSTRACT: Molecular dynamic (MD) simulations have become a common tool to study the pathway of ligand entry to the orthosteric binding site of G protein-coupled receptors. Here, we have combined MD simulations and site-directed mutagenesis to study the binding process of the potent JWH-133 agonist to the cannabinoid CB₂ receptor (CB₂R). In CB₂R, the N-terminus and extracellular loop 2 fold over the ligand binding pocket, blocking access to the binding cavity from the extracellular environment. We, thus, hypothesized that the binding pathway is a multistage process consisting of the hydrophobic ligand diffusing in the lipid bilayer to contact a lipid-facing vestibule, from which the ligand enters an allosteric site inside the transmembrane bundle through a tunnel form

SUBMITTER: Casajuana-Martin N 

PROVIDER: S-EPMC9709915 | biostudies-literature | 2022 Nov

REPOSITORIES: biostudies-literature