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http://hdl.handle.net/2445/191975
Title: | A Single Point Mutation Blocks the Entrance of Ligands to the Cannabinoid CB2 Receptor via the Lipid Bilayer |
Author: | 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 |
Keywords: | Dinàmica molecular Bicapes lipídiques Mutació (Biologia) Molecular dynamics Lipid bilayers Mutation (Biology) |
Issue Date: | 28-Nov-2022 |
Publisher: | American Chemical Society |
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. |
Note: | Versió postprint del document publicat a: https://doi.org/10.1021/acs.jcim.2c00865 |
It is part of: | Journal of Chemical Information and Modeling, 2022, vol. 62, num. 22, p. 5771-5779 |
URI: | http://hdl.handle.net/2445/191975 |
Related resource: | https://doi.org/10.1021/acs.jcim.2c00865 |
ISSN: | 1549-9596 |
Appears in Collections: | Articles publicats en revistes (Bioquímica i Biomedicina Molecular) |
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