Ligand chain length drives activation of lipid G protein-coupled receptors

Abstract Sphingosine-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 impl...

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Autores principales:	Anastassia Troupiotis-Tsaïlaki, Julian Zachmann, Inés González-Gil, Angel Gonzalez, Silvia Ortega-Gutiérrez, Maria L. López-Rodríguez, Leonardo Pardo, Cedric Govaerts
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/a21d0cf6f7474819a25877758a9730b9
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spelling	oai:doaj.org-article:a21d0cf6f7474819a25877758a9730b92021-12-02T12:32:50ZLigand chain length drives activation of lipid G protein-coupled receptors10.1038/s41598-017-02104-52045-2322https://doaj.org/article/a21d0cf6f7474819a25877758a9730b92017-05-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-02104-5https://doaj.org/toc/2045-2322Abstract Sphingosine-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.Anastassia Troupiotis-TsaïlakiJulian ZachmannInés González-GilAngel GonzalezSilvia Ortega-GutiérrezMaria L. López-RodríguezLeonardo PardoCedric GovaertsNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-13 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Anastassia Troupiotis-Tsaïlaki Julian Zachmann Inés González-Gil Angel Gonzalez Silvia Ortega-Gutiérrez Maria L. López-Rodríguez Leonardo Pardo Cedric Govaerts Ligand chain length drives activation of lipid G protein-coupled receptors
description	Abstract Sphingosine-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.
format	article
author	Anastassia Troupiotis-Tsaïlaki Julian Zachmann Inés González-Gil Angel Gonzalez Silvia Ortega-Gutiérrez Maria L. López-Rodríguez Leonardo Pardo Cedric Govaerts
author_facet	Anastassia Troupiotis-Tsaïlaki Julian Zachmann Inés González-Gil Angel Gonzalez Silvia Ortega-Gutiérrez Maria L. López-Rodríguez Leonardo Pardo Cedric Govaerts
author_sort	Anastassia Troupiotis-Tsaïlaki
title	Ligand chain length drives activation of lipid G protein-coupled receptors
title_short	Ligand chain length drives activation of lipid G protein-coupled receptors
title_full	Ligand chain length drives activation of lipid G protein-coupled receptors
title_fullStr	Ligand chain length drives activation of lipid G protein-coupled receptors
title_full_unstemmed	Ligand chain length drives activation of lipid G protein-coupled receptors
title_sort	ligand chain length drives activation of lipid g protein-coupled receptors
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/a21d0cf6f7474819a25877758a9730b9
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Ligand chain length drives activation of lipid G protein-coupled receptors

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