Insights into the substrate binding mechanism of SULT1A1 through molecular dynamics with excited normal modes simulations

Abstract Sulfotransferases (SULTs) are phase II drug-metabolizing enzymes catalyzing the sulfoconjugation from the co-factor 3′-phosphoadenosine 5′-phosphosulfate (PAPS) to a substrate. It has been previously suggested that a considerable shift of SULT structure caused by PAPS binding could control...

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Autores principales:	Balint Dudas, Daniel Toth, David Perahia, Arnaud B. Nicot, Erika Balog, Maria A. Miteva
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/ece2219aba824e04a7c747cf0ec901a5
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spelling	oai:doaj.org-article:ece2219aba824e04a7c747cf0ec901a52021-12-02T17:12:17ZInsights into the substrate binding mechanism of SULT1A1 through molecular dynamics with excited normal modes simulations10.1038/s41598-021-92480-w2045-2322https://doaj.org/article/ece2219aba824e04a7c747cf0ec901a52021-06-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-92480-whttps://doaj.org/toc/2045-2322Abstract Sulfotransferases (SULTs) are phase II drug-metabolizing enzymes catalyzing the sulfoconjugation from the co-factor 3′-phosphoadenosine 5′-phosphosulfate (PAPS) to a substrate. It has been previously suggested that a considerable shift of SULT structure caused by PAPS binding could control the capability of SULT to bind large substrates. We employed molecular dynamics (MD) simulations and the recently developed approach of MD with excited normal modes (MDeNM) to elucidate molecular mechanisms guiding the recognition of diverse substrates and inhibitors by SULT1A1. MDeNM allowed exploring an extended conformational space of PAPS-bound SULT1A1, which has not been achieved up to now by using classical MD. The generated ensembles combined with docking of 132 SULT1A1 ligands shed new light on substrate and inhibitor binding mechanisms. Unexpectedly, our simulations and analyses on binding of the substrates estradiol and fulvestrant demonstrated that large conformational changes of the PAPS-bound SULT1A1 could occur independently of the co-factor movements that could be sufficient to accommodate large substrates as fulvestrant. Such structural displacements detected by the MDeNM simulations in the presence of the co-factor suggest that a wider range of drugs could be recognized by PAPS-bound SULT1A1 and highlight the utility of including MDeNM in protein–ligand interactions studies where major rearrangements are expected.Balint DudasDaniel TothDavid PerahiaArnaud B. NicotErika BalogMaria A. MitevaNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-13 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Balint Dudas Daniel Toth David Perahia Arnaud B. Nicot Erika Balog Maria A. Miteva Insights into the substrate binding mechanism of SULT1A1 through molecular dynamics with excited normal modes simulations
description	Abstract Sulfotransferases (SULTs) are phase II drug-metabolizing enzymes catalyzing the sulfoconjugation from the co-factor 3′-phosphoadenosine 5′-phosphosulfate (PAPS) to a substrate. It has been previously suggested that a considerable shift of SULT structure caused by PAPS binding could control the capability of SULT to bind large substrates. We employed molecular dynamics (MD) simulations and the recently developed approach of MD with excited normal modes (MDeNM) to elucidate molecular mechanisms guiding the recognition of diverse substrates and inhibitors by SULT1A1. MDeNM allowed exploring an extended conformational space of PAPS-bound SULT1A1, which has not been achieved up to now by using classical MD. The generated ensembles combined with docking of 132 SULT1A1 ligands shed new light on substrate and inhibitor binding mechanisms. Unexpectedly, our simulations and analyses on binding of the substrates estradiol and fulvestrant demonstrated that large conformational changes of the PAPS-bound SULT1A1 could occur independently of the co-factor movements that could be sufficient to accommodate large substrates as fulvestrant. Such structural displacements detected by the MDeNM simulations in the presence of the co-factor suggest that a wider range of drugs could be recognized by PAPS-bound SULT1A1 and highlight the utility of including MDeNM in protein–ligand interactions studies where major rearrangements are expected.
format	article
author	Balint Dudas Daniel Toth David Perahia Arnaud B. Nicot Erika Balog Maria A. Miteva
author_facet	Balint Dudas Daniel Toth David Perahia Arnaud B. Nicot Erika Balog Maria A. Miteva
author_sort	Balint Dudas
title	Insights into the substrate binding mechanism of SULT1A1 through molecular dynamics with excited normal modes simulations
title_short	Insights into the substrate binding mechanism of SULT1A1 through molecular dynamics with excited normal modes simulations
title_full	Insights into the substrate binding mechanism of SULT1A1 through molecular dynamics with excited normal modes simulations
title_fullStr	Insights into the substrate binding mechanism of SULT1A1 through molecular dynamics with excited normal modes simulations
title_full_unstemmed	Insights into the substrate binding mechanism of SULT1A1 through molecular dynamics with excited normal modes simulations
title_sort	insights into the substrate binding mechanism of sult1a1 through molecular dynamics with excited normal modes simulations
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/ece2219aba824e04a7c747cf0ec901a5
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Insights into the substrate binding mechanism of SULT1A1 through molecular dynamics with excited normal modes simulations

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