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http://hdl.handle.net/2445/191975
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DC Field | Value | Language |
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dc.contributor.author | Casajuana-Martin, Nil | - |
dc.contributor.author | Navarro Brugal, Gemma | - |
dc.contributor.author | González Ureña, A. | - |
dc.contributor.author | Llinàs Del Torrent Masachs, Clàudia | - |
dc.contributor.author | Gómez-Autet, Marc | - |
dc.contributor.author | Quintana García, Aleix | - |
dc.contributor.author | Franco Fernández, Rafael | - |
dc.contributor.author | Pardo, Leonardo | - |
dc.date.accessioned | 2023-01-10T08:44:44Z | - |
dc.date.available | 2023-11-28T06:10:21Z | - |
dc.date.issued | 2022-11-28 | - |
dc.identifier.issn | 1549-9596 | - |
dc.identifier.uri | http://hdl.handle.net/2445/191975 | - |
dc.description.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. | - |
dc.format.extent | 9 p. | - |
dc.format.mimetype | application/pdf | - |
dc.language.iso | eng | - |
dc.publisher | American Chemical Society | - |
dc.relation.isformatof | Versió postprint del document publicat a: https://doi.org/10.1021/acs.jcim.2c00865 | - |
dc.relation.ispartof | Journal of Chemical Information and Modeling, 2022, vol. 62, num. 22, p. 5771-5779 | - |
dc.relation.uri | https://doi.org/10.1021/acs.jcim.2c00865 | - |
dc.rights | (c) American Chemical Society , 2022 | - |
dc.rights.uri | http://creativecommons.org/licenses/by/3.0/es/ | * |
dc.source | Articles publicats en revistes (Bioquímica i Biomedicina Molecular) | - |
dc.subject.classification | Dinàmica molecular | - |
dc.subject.classification | Bicapes lipídiques | - |
dc.subject.classification | Mutació (Biologia) | - |
dc.subject.other | Molecular dynamics | - |
dc.subject.other | Lipid bilayers | - |
dc.subject.other | Mutation (Biology) | - |
dc.title | A Single Point Mutation Blocks the Entrance of Ligands to the Cannabinoid CB2 Receptor via the Lipid Bilayer | - |
dc.type | info:eu-repo/semantics/article | - |
dc.type | info:eu-repo/semantics/acceptedVersion | - |
dc.identifier.idgrec | 727689 | - |
dc.date.updated | 2023-01-10T08:44:44Z | - |
dc.rights.accessRights | info:eu-repo/semantics/openAccess | - |
Appears in Collections: | Articles publicats en revistes (Bioquímica i Biomedicina Molecular) |
Files in This Item:
File | Description | Size | Format | |
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727689.pdf | 4.95 MB | Adobe PDF | View/Open |
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