The role of water in activation mechanism of human N-formyl peptide receptor 1 (FPR1) based on molecular dynamics simulations.

The Formyl Peptide Receptor 1 (FPR1) is an important chemotaxis receptor involved in various aspects of host defense and inflammatory processes. We constructed a model of FPR1 using as a novel template the chemokine receptor CXCR4 from the same branch of the phylogenetic tree of G-protein-coupled re...

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Autores principales:	Shuguang Yuan, Umesh Ghoshdastider, Bartosz Trzaskowski, Dorota Latek, Aleksander Debinski, Wojciech Pulawski, Rongliang Wu, Volker Gerke, Slawomir Filipek
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2012
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/cc8f9f9a470741c299a4184e46b8e740
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spelling	oai:doaj.org-article:cc8f9f9a470741c299a4184e46b8e7402021-11-18T08:07:40ZThe role of water in activation mechanism of human N-formyl peptide receptor 1 (FPR1) based on molecular dynamics simulations.1932-620310.1371/journal.pone.0047114https://doaj.org/article/cc8f9f9a470741c299a4184e46b8e7402012-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23189124/?tool=EBIhttps://doaj.org/toc/1932-6203The Formyl Peptide Receptor 1 (FPR1) is an important chemotaxis receptor involved in various aspects of host defense and inflammatory processes. We constructed a model of FPR1 using as a novel template the chemokine receptor CXCR4 from the same branch of the phylogenetic tree of G-protein-coupled receptors. The previously employed template of rhodopsin contained a bulge at the extracellular part of TM2 which directly influenced binding of ligands. We also conducted molecular dynamics (MD) simulations of FPR1 in the apo form as well as in a form complexed with the agonist fMLF and the antagonist tBocMLF in the model membrane. During all MD simulation of the fMLF-FPR1 complex a water molecule transiently bridged the hydrogen bond between W254(6.48) and N108(3.35) in the middle of the receptor. We also observed a change in the cytoplasmic part of FPR1 of a rotamer of the Y301(7.53) residue (tyrosine rotamer switch). This effect facilitated movement of more water molecules toward the receptor center. Such rotamer of Y301(7.53) was not observed in any crystal structures of GPCRs which can suggest that this state is temporarily formed to pass the water molecules during the activation process. The presence of a distance between agonist and residues R201(5.38) and R205(5.42) on helix TM5 may suggest that the activation of FPR1 is similar to the activation of β-adrenergic receptors since their agonists are separated from serine residues on helix TM5. The removal of water molecules bridging these interactions in FPR1 can result in shrinking of the binding site during activation similarly to the shrinking observed in β-ARs. The number of GPCR crystal structures with agonists is still scarce so the designing of new ligands with agonistic properties is hampered, therefore homology modeling and docking can provide suitable models. Additionally, the MD simulations can be beneficial to outline the mechanisms of receptor activation and the agonist/antagonist sensing.Shuguang YuanUmesh GhoshdastiderBartosz TrzaskowskiDorota LatekAleksander DebinskiWojciech PulawskiRongliang WuVolker GerkeSlawomir FilipekPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 7, Iss 11, p e47114 (2012)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Shuguang Yuan Umesh Ghoshdastider Bartosz Trzaskowski Dorota Latek Aleksander Debinski Wojciech Pulawski Rongliang Wu Volker Gerke Slawomir Filipek The role of water in activation mechanism of human N-formyl peptide receptor 1 (FPR1) based on molecular dynamics simulations.
description	The Formyl Peptide Receptor 1 (FPR1) is an important chemotaxis receptor involved in various aspects of host defense and inflammatory processes. We constructed a model of FPR1 using as a novel template the chemokine receptor CXCR4 from the same branch of the phylogenetic tree of G-protein-coupled receptors. The previously employed template of rhodopsin contained a bulge at the extracellular part of TM2 which directly influenced binding of ligands. We also conducted molecular dynamics (MD) simulations of FPR1 in the apo form as well as in a form complexed with the agonist fMLF and the antagonist tBocMLF in the model membrane. During all MD simulation of the fMLF-FPR1 complex a water molecule transiently bridged the hydrogen bond between W254(6.48) and N108(3.35) in the middle of the receptor. We also observed a change in the cytoplasmic part of FPR1 of a rotamer of the Y301(7.53) residue (tyrosine rotamer switch). This effect facilitated movement of more water molecules toward the receptor center. Such rotamer of Y301(7.53) was not observed in any crystal structures of GPCRs which can suggest that this state is temporarily formed to pass the water molecules during the activation process. The presence of a distance between agonist and residues R201(5.38) and R205(5.42) on helix TM5 may suggest that the activation of FPR1 is similar to the activation of β-adrenergic receptors since their agonists are separated from serine residues on helix TM5. The removal of water molecules bridging these interactions in FPR1 can result in shrinking of the binding site during activation similarly to the shrinking observed in β-ARs. The number of GPCR crystal structures with agonists is still scarce so the designing of new ligands with agonistic properties is hampered, therefore homology modeling and docking can provide suitable models. Additionally, the MD simulations can be beneficial to outline the mechanisms of receptor activation and the agonist/antagonist sensing.
format	article
author	Shuguang Yuan Umesh Ghoshdastider Bartosz Trzaskowski Dorota Latek Aleksander Debinski Wojciech Pulawski Rongliang Wu Volker Gerke Slawomir Filipek
author_facet	Shuguang Yuan Umesh Ghoshdastider Bartosz Trzaskowski Dorota Latek Aleksander Debinski Wojciech Pulawski Rongliang Wu Volker Gerke Slawomir Filipek
author_sort	Shuguang Yuan
title	The role of water in activation mechanism of human N-formyl peptide receptor 1 (FPR1) based on molecular dynamics simulations.
title_short	The role of water in activation mechanism of human N-formyl peptide receptor 1 (FPR1) based on molecular dynamics simulations.
title_full	The role of water in activation mechanism of human N-formyl peptide receptor 1 (FPR1) based on molecular dynamics simulations.
title_fullStr	The role of water in activation mechanism of human N-formyl peptide receptor 1 (FPR1) based on molecular dynamics simulations.
title_full_unstemmed	The role of water in activation mechanism of human N-formyl peptide receptor 1 (FPR1) based on molecular dynamics simulations.
title_sort	role of water in activation mechanism of human n-formyl peptide receptor 1 (fpr1) based on molecular dynamics simulations.
publisher	Public Library of Science (PLoS)
publishDate	2012
url	https://doaj.org/article/cc8f9f9a470741c299a4184e46b8e740
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The role of water in activation mechanism of human N-formyl peptide receptor 1 (FPR1) based on molecular dynamics simulations.

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