Molecular mechanism of proton-coupled ligand translocation by the bacterial efflux pump EmrE.

The current surge in bacterial multi-drug resistance (MDR) is one of the largest challenges to public health, threatening to render ineffective many therapies we rely on for treatment of serious infections. Understanding different factors that contribute to MDR is hence crucial from the global "...

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Autores principales:	Jakub Jurasz, Maciej Bagiński, Jacek Czub, Miłosz Wieczór
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2021
Materias:	Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/25041ead47754663a4b0623fc0198db2
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spelling	oai:doaj.org-article:25041ead47754663a4b0623fc0198db22021-11-25T05:40:33ZMolecular mechanism of proton-coupled ligand translocation by the bacterial efflux pump EmrE.1553-734X1553-735810.1371/journal.pcbi.1009454https://doaj.org/article/25041ead47754663a4b0623fc0198db22021-10-01T00:00:00Zhttps://doi.org/10.1371/journal.pcbi.1009454https://doaj.org/toc/1553-734Xhttps://doaj.org/toc/1553-7358The current surge in bacterial multi-drug resistance (MDR) is one of the largest challenges to public health, threatening to render ineffective many therapies we rely on for treatment of serious infections. Understanding different factors that contribute to MDR is hence crucial from the global "one health" perspective. In this contribution, we focus on the prototypical broad-selectivity proton-coupled antiporter EmrE, one of the smallest known ligand transporters that confers resistance to aromatic cations in a number of clinically relevant species. As an asymmetric homodimer undergoing an "alternating access" protomer-swap conformational change, it serves as a model for the mechanistic understanding of more complex drug transporters. Here, we present a free energy and solvent accessibility analysis that indicates the presence of two complementary ligand translocation pathways that remain operative in a broad range of conditions. Our simulations show a previously undescribed desolvated apo state and anticorrelated accessibility in the ligand-bound state, explaining on a structural level why EmrE does not disrupt the pH gradient through futile proton transfer. By comparing the behavior of a number of model charged and/or aromatic ligands, we also explain the origin of selectivity of EmrE towards a broad class of aromatic cations. Finally, we explore unbiased pathways of ligand entry and exit to identify correlated structural changes implicated in ligand binding and release, as well as characterize key intermediates of occupancy changes.Jakub JuraszMaciej BagińskiJacek CzubMiłosz WieczórPublic Library of Science (PLoS)articleBiology (General)QH301-705.5ENPLoS Computational Biology, Vol 17, Iss 10, p e1009454 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Biology (General) QH301-705.5
spellingShingle	Biology (General) QH301-705.5 Jakub Jurasz Maciej Bagiński Jacek Czub Miłosz Wieczór Molecular mechanism of proton-coupled ligand translocation by the bacterial efflux pump EmrE.
description	The current surge in bacterial multi-drug resistance (MDR) is one of the largest challenges to public health, threatening to render ineffective many therapies we rely on for treatment of serious infections. Understanding different factors that contribute to MDR is hence crucial from the global "one health" perspective. In this contribution, we focus on the prototypical broad-selectivity proton-coupled antiporter EmrE, one of the smallest known ligand transporters that confers resistance to aromatic cations in a number of clinically relevant species. As an asymmetric homodimer undergoing an "alternating access" protomer-swap conformational change, it serves as a model for the mechanistic understanding of more complex drug transporters. Here, we present a free energy and solvent accessibility analysis that indicates the presence of two complementary ligand translocation pathways that remain operative in a broad range of conditions. Our simulations show a previously undescribed desolvated apo state and anticorrelated accessibility in the ligand-bound state, explaining on a structural level why EmrE does not disrupt the pH gradient through futile proton transfer. By comparing the behavior of a number of model charged and/or aromatic ligands, we also explain the origin of selectivity of EmrE towards a broad class of aromatic cations. Finally, we explore unbiased pathways of ligand entry and exit to identify correlated structural changes implicated in ligand binding and release, as well as characterize key intermediates of occupancy changes.
format	article
author	Jakub Jurasz Maciej Bagiński Jacek Czub Miłosz Wieczór
author_facet	Jakub Jurasz Maciej Bagiński Jacek Czub Miłosz Wieczór
author_sort	Jakub Jurasz
title	Molecular mechanism of proton-coupled ligand translocation by the bacterial efflux pump EmrE.
title_short	Molecular mechanism of proton-coupled ligand translocation by the bacterial efflux pump EmrE.
title_full	Molecular mechanism of proton-coupled ligand translocation by the bacterial efflux pump EmrE.
title_fullStr	Molecular mechanism of proton-coupled ligand translocation by the bacterial efflux pump EmrE.
title_full_unstemmed	Molecular mechanism of proton-coupled ligand translocation by the bacterial efflux pump EmrE.
title_sort	molecular mechanism of proton-coupled ligand translocation by the bacterial efflux pump emre.
publisher	Public Library of Science (PLoS)
publishDate	2021
url	https://doaj.org/article/25041ead47754663a4b0623fc0198db2
work_keys_str_mv	AT jakubjurasz molecularmechanismofprotoncoupledligandtranslocationbythebacterialeffluxpumpemre AT maciejbaginski molecularmechanismofprotoncoupledligandtranslocationbythebacterialeffluxpumpemre AT jacekczub molecularmechanismofprotoncoupledligandtranslocationbythebacterialeffluxpumpemre AT miłoszwieczor molecularmechanismofprotoncoupledligandtranslocationbythebacterialeffluxpumpemre
_version_	1718414506232643584

Molecular mechanism of proton-coupled ligand translocation by the bacterial efflux pump EmrE.

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