Please use this identifier to cite or link to this item: https://hdl.handle.net/20.500.12530/41632
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dc.contributor.authorTroupiotis-Tsaïlaki, Anastassia
dc.contributor.authorZachmann, Julian
dc.contributor.authorGonzález-Gil, Inés
dc.contributor.authorGonzalez, Angel
dc.contributor.authorOrtega-Gutiérrez, Silvia
dc.contributor.authorLópez-Rodríguez, Maria L
dc.contributor.authorPardo, Leonardo
dc.contributor.authorGovaerts, Cedric
dc.date.accessioned2019-08-02T09:53:50Z-
dc.date.available2019-08-02T09:53:50Z-
dc.date.issued2017
dc.identifier.citationSci Rep.2017 05;(7)1:2020
dc.identifier.urihttps://hdl.handle.net/20.500.12530/41632-
dc.description.abstractSphingosine-1-phosphate (S1P) is a lipid mediator that can activate five cell membrane G protein-coupled receptors (GPCRs) which carry a variety of essential functions and are promising drug targets. S1P is composed of a polar zwitterionic head-group and a hydrophobic alkyl chain. This implies an activation mechanism of its cognate receptor that must be significantly different from what is known for prototypical GPCRs (ie receptor to small hydrophilic ligands). Here we aim to identify the structural features responsible for S1P agonism by combining molecular dynamics simulations and functional assays using S1P analogs of different alkyl chain lengths. We propose that high affinity binding involves polar interactions between the lipid head-group and receptor side chains while activation is due to hydrophobic interactions between the lipid tail and residues in a distinct binding site. We observe that ligand efficacy is directly related to alkyl chain length but also varies with receptor subtypes in correlation with the size of this binding pocket. Integrating experimental and computational data, we propose an activation mechanism for the S1P receptors involving agonist-induced conformational events that are conserved throughout class A GPCRs.
dc.language.isoeng
dc.rightsopenAccess-
dc.subject.meshAnimals
dc.subject.meshBinding Sites
dc.subject.meshCHO Cells
dc.subject.meshCricetulus
dc.subject.meshLigands
dc.subject.meshLipid Metabolism
dc.subject.meshLipids
dc.subject.meshLysophospholipids
dc.subject.meshMolecular Conformation
dc.subject.meshMolecular Docking Simulation
dc.subject.meshMolecular Dynamics Simulation
dc.subject.meshMolecular Structure
dc.subject.meshProtein Binding
dc.subject.meshReceptors, G-Protein-Coupled
dc.subject.meshReceptors, Lysosphingolipid
dc.subject.meshSphingosine
dc.subject.meshStructure-Activity Relationship
dc.titleLigand chain length drives activation of lipid G protein-coupled receptors.
dc.typeArtículo
dc.identifier.pubmedID28515494
dc.format.volume7
dc.format.page2020
dc.identifier.e-issn2045-2322
dc.identifier.journalScientific reports
dc.identifier.doi10.1038/s41598-017-02104-5
dc.format.number1
dc.identifier.pmcPMC5435731
dc.pubmedtypeJournal Article
dc.pubmedtypeResearch Support, Non-U.S. Gov't
Appears in Collections:Fundaciones e Institutos de Investigación > IIS H. U. 12 de Octubre > Artículos

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