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Si us plau utilitzeu sempre aquest identificador per citar o enllaçar aquest document: https://hdl.handle.net/2445/191975
A Single Point Mutation Blocks the Entrance of Ligands to the Cannabinoid CB2 Receptor via the Lipid Bilayer
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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.
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CASAJUANA-MARTIN, Nil, NAVARRO BRUGAL, Gemma, GONZÁLEZ UREÑA, A., LLINÀS DEL TORRENT MASACHS, Clàudia, GÓMEZ-AUTET, Marc, QUINTANA GARCÍA, Aleix, FRANCO FERNÁNDEZ, Rafael, PARDO, Leonardo. A Single Point Mutation Blocks the Entrance of Ligands to the Cannabinoid CB2 Receptor via the Lipid Bilayer. _Journal of Chemical Information and Modeling_. 2022. Vol. 62, núm. 22, pàgs. 5771-5779. [consulta: 27 de gener de 2026]. ISSN: 1549-9596. [Disponible a: https://hdl.handle.net/2445/191975]