Web of Science: 10 citations, Scopus: 11 citations, Google Scholar: citations,
Ligand chain length drives activation of lipid G protein-coupled receptors
Troupiotis-Tsaïlaki, Anastassia (Université Libre de Bruxelles. Laboratoire de Structure et Fonction des Membranes Biologiques)
Zachmann, Julian (Universitat Autònoma de Barcelona. Laboratori de Medicina Computacional)
González-Gil, Inés (Universidad Complutense de Madrid. Departamento de Química Orgánica I)
González, Ángel (Universitat Autònoma de Barcelona. Laboratori de Medicina Computacional)
Ortega Gutiérrez, Silvia (Universidad Complutense de Madrid. Departamento de Química Orgánica I)
López-Rodríguez, María L. (Universidad Complutense de Madrid. Departamento de Química Orgánica I)
Pardo Carrasco, Leonardo (Universitat Autònoma de Barcelona. Laboratori de Medicina Computacional)
Govaerts, Cedric (Université Libre de Bruxelles. Laboratoire de Structure et Fonction des Membranes Biologiques)

Date: 2017
Abstract: Sphingosine-1-phosphate (S1P) is a lipid mediator that can activate five cell membrane G proteincoupled 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.
Rights: Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original. Creative Commons
Language: Anglès.
Document: article ; recerca ; publishedVersion
Published in: Scientific Reports, Vol. 7 (2017) , art. 2020, ISSN 2045-2322

DOI: 10.1038/s41598-017-02104-5
PMID: 28515494


13 p, 1.8 MB

The record appears in these collections:
Articles > Research articles
Articles > Published articles

 Record created 2019-09-10, last modified 2019-10-08



   Favorit i Compartir