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• W4307504013 endingPage "5779" @default.
• W4307504013 startingPage "5771" @default.
• W4307504013 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 formed between TMs 1 and 7 and finally moving from the allosteric to the orthosteric binding cavity. This pathway was experimentally validated by the Ala2827.36Phe mutation that blocks the entrance of the ligand, as JWH-133 was not able to decrease the forskolin-induced cAMP levels in cells expressing the mutant receptor. This proposed ligand entry pathway defines transient binding sites that are potential cavities for the design of synthetic modulators." @default.
• W4307504013 created "2022-11-02" @default.
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• W4307504013 date "2022-10-27" @default.
• W4307504013 modified "2023-10-16" @default.
• W4307504013 title "A Single Point Mutation Blocks the Entrance of Ligands to the Cannabinoid CB₂ Receptor via the Lipid Bilayer" @default.
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• W4307504013 doi "https://doi.org/10.1021/acs.jcim.2c00865" @default.
• W4307504013 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/36302505" @default.
• W4307504013 hasPublicationYear "2022" @default.
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