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Molecular rationale for the impairment of the MexAB-OprM efflux pump by a single mutation in MexA
Efflux pumps of the Resistance-Nodulation-cell Division (RND) superfamily contribute to intrinsic and acquired resistance in Gram-negative pathogens by expelling chemically unrelated antibiotics with high efficiency. They are tripartite systems constituted by an inner-membrane-anchored transporter,...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Research Network of Computational and Structural Biotechnology
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8717590/ https://www.ncbi.nlm.nih.gov/pubmed/35024097 http://dx.doi.org/10.1016/j.csbj.2021.11.042 |
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author | Cacciotto, Pierpaolo Basciu, Andrea Oliva, Francesco Malloci, Giuliano Zacharias, Martin Ruggerone, Paolo Vargiu, Attilio V. |
author_facet | Cacciotto, Pierpaolo Basciu, Andrea Oliva, Francesco Malloci, Giuliano Zacharias, Martin Ruggerone, Paolo Vargiu, Attilio V. |
author_sort | Cacciotto, Pierpaolo |
collection | PubMed |
description | Efflux pumps of the Resistance-Nodulation-cell Division (RND) superfamily contribute to intrinsic and acquired resistance in Gram-negative pathogens by expelling chemically unrelated antibiotics with high efficiency. They are tripartite systems constituted by an inner-membrane-anchored transporter, an outer membrane factor protein, and a membrane fusion protein. Multimerization of the membrane fusion protein is an essential prerequisite for full functionality of these efflux pumps. In this work, we employed complementary computational techniques to investigate the stability of a dimeric unit of MexA (the membrane fusion protein of the MexAB-OprM RND efflux pump of Pseudomonas aeruginosa), and to provide a molecular rationale for the effect of the G72S substitution, which affects MexAB-OprM functionality by impairing the assembly of MexA. Our findings indicate that: i) dimers of this protein are stable in multiple µs-long molecular dynamics simulations; ii) the mutation drastically alters the conformational equilibrium of MexA, favouring a collapsed conformation that is unlikely to form dimers or higher order assemblies. Unveiling the mechanistic aspects underlying large conformational distortions induced by minor sequence changes is informative to efforts at interfering with the activity of this elusive bacterial weapon. In this respect, our work further confirms how molecular simulations can give important contribution and useful insights to characterize the mechanism of highly complex biological systems. |
format | Online Article Text |
id | pubmed-8717590 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Research Network of Computational and Structural Biotechnology |
record_format | MEDLINE/PubMed |
spelling | pubmed-87175902022-01-11 Molecular rationale for the impairment of the MexAB-OprM efflux pump by a single mutation in MexA Cacciotto, Pierpaolo Basciu, Andrea Oliva, Francesco Malloci, Giuliano Zacharias, Martin Ruggerone, Paolo Vargiu, Attilio V. Comput Struct Biotechnol J Research Article Efflux pumps of the Resistance-Nodulation-cell Division (RND) superfamily contribute to intrinsic and acquired resistance in Gram-negative pathogens by expelling chemically unrelated antibiotics with high efficiency. They are tripartite systems constituted by an inner-membrane-anchored transporter, an outer membrane factor protein, and a membrane fusion protein. Multimerization of the membrane fusion protein is an essential prerequisite for full functionality of these efflux pumps. In this work, we employed complementary computational techniques to investigate the stability of a dimeric unit of MexA (the membrane fusion protein of the MexAB-OprM RND efflux pump of Pseudomonas aeruginosa), and to provide a molecular rationale for the effect of the G72S substitution, which affects MexAB-OprM functionality by impairing the assembly of MexA. Our findings indicate that: i) dimers of this protein are stable in multiple µs-long molecular dynamics simulations; ii) the mutation drastically alters the conformational equilibrium of MexA, favouring a collapsed conformation that is unlikely to form dimers or higher order assemblies. Unveiling the mechanistic aspects underlying large conformational distortions induced by minor sequence changes is informative to efforts at interfering with the activity of this elusive bacterial weapon. In this respect, our work further confirms how molecular simulations can give important contribution and useful insights to characterize the mechanism of highly complex biological systems. Research Network of Computational and Structural Biotechnology 2021-12-03 /pmc/articles/PMC8717590/ /pubmed/35024097 http://dx.doi.org/10.1016/j.csbj.2021.11.042 Text en © 2021 The Authors https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Research Article Cacciotto, Pierpaolo Basciu, Andrea Oliva, Francesco Malloci, Giuliano Zacharias, Martin Ruggerone, Paolo Vargiu, Attilio V. Molecular rationale for the impairment of the MexAB-OprM efflux pump by a single mutation in MexA |
title | Molecular rationale for the impairment of the MexAB-OprM efflux pump by a single mutation in MexA |
title_full | Molecular rationale for the impairment of the MexAB-OprM efflux pump by a single mutation in MexA |
title_fullStr | Molecular rationale for the impairment of the MexAB-OprM efflux pump by a single mutation in MexA |
title_full_unstemmed | Molecular rationale for the impairment of the MexAB-OprM efflux pump by a single mutation in MexA |
title_short | Molecular rationale for the impairment of the MexAB-OprM efflux pump by a single mutation in MexA |
title_sort | molecular rationale for the impairment of the mexab-oprm efflux pump by a single mutation in mexa |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8717590/ https://www.ncbi.nlm.nih.gov/pubmed/35024097 http://dx.doi.org/10.1016/j.csbj.2021.11.042 |
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