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Common recognition topology of mex transporters of Pseudomonas aeruginosa revealed by molecular modelling
The secondary transporters of the resistance-nodulation-cell division (RND) superfamily mediate multidrug resistance in Gram-negative bacteria like Pseudomonas aeruginosa. Among these RND transporters, MexB, MexF, and MexY, with partly overlapping specificities, have been implicated in pathogenicity...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2022
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9691783/ https://www.ncbi.nlm.nih.gov/pubmed/36438787 http://dx.doi.org/10.3389/fphar.2022.1021916 |
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author | Catte, Andrea K. Ramaswamy, Venkata Vargiu, Attilio Vittorio Malloci, Giuliano Bosin, Andrea Ruggerone, Paolo |
author_facet | Catte, Andrea K. Ramaswamy, Venkata Vargiu, Attilio Vittorio Malloci, Giuliano Bosin, Andrea Ruggerone, Paolo |
author_sort | Catte, Andrea |
collection | PubMed |
description | The secondary transporters of the resistance-nodulation-cell division (RND) superfamily mediate multidrug resistance in Gram-negative bacteria like Pseudomonas aeruginosa. Among these RND transporters, MexB, MexF, and MexY, with partly overlapping specificities, have been implicated in pathogenicity. Only the structure of the former has been resolved experimentally, which together with the lack of data about the functional dynamics of the full set of transporters, limited a systematic investigation of the molecular determinants defining their peculiar and shared features. In a previous work (Ramaswamy et al., Front. Microbiol., 2018, 9, 1144), we compared at an atomistic level the two main putative recognition sites (named access and deep binding pockets) of MexB and MexY. In this work, we expand the comparison by performing extended molecular dynamics (MD) simulations of these transporters and the pathologically relevant transporter MexF. We employed a more realistic model of the inner phospholipid membrane of P. aeruginosa and more accurate force-fields. To elucidate structure/dynamics-activity relationships we performed physico-chemical analyses and mapped the binding propensities of several organic probes on all transporters. Our data revealed the presence, also in MexF, of a few multifunctional sites at locations equivalent to the access and deep binding pockets detected in MexB. Furthermore, we report for the first time about the multidrug binding abilities of two out of five gates of the channels deputed to peripheral (early) recognition of substrates. Overall, our findings help to define a common “recognition topology” characterizing Mex transporters, which can be exploited to optimize transport and inhibition propensities of antimicrobial compounds. |
format | Online Article Text |
id | pubmed-9691783 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-96917832022-11-26 Common recognition topology of mex transporters of Pseudomonas aeruginosa revealed by molecular modelling Catte, Andrea K. Ramaswamy, Venkata Vargiu, Attilio Vittorio Malloci, Giuliano Bosin, Andrea Ruggerone, Paolo Front Pharmacol Pharmacology The secondary transporters of the resistance-nodulation-cell division (RND) superfamily mediate multidrug resistance in Gram-negative bacteria like Pseudomonas aeruginosa. Among these RND transporters, MexB, MexF, and MexY, with partly overlapping specificities, have been implicated in pathogenicity. Only the structure of the former has been resolved experimentally, which together with the lack of data about the functional dynamics of the full set of transporters, limited a systematic investigation of the molecular determinants defining their peculiar and shared features. In a previous work (Ramaswamy et al., Front. Microbiol., 2018, 9, 1144), we compared at an atomistic level the two main putative recognition sites (named access and deep binding pockets) of MexB and MexY. In this work, we expand the comparison by performing extended molecular dynamics (MD) simulations of these transporters and the pathologically relevant transporter MexF. We employed a more realistic model of the inner phospholipid membrane of P. aeruginosa and more accurate force-fields. To elucidate structure/dynamics-activity relationships we performed physico-chemical analyses and mapped the binding propensities of several organic probes on all transporters. Our data revealed the presence, also in MexF, of a few multifunctional sites at locations equivalent to the access and deep binding pockets detected in MexB. Furthermore, we report for the first time about the multidrug binding abilities of two out of five gates of the channels deputed to peripheral (early) recognition of substrates. Overall, our findings help to define a common “recognition topology” characterizing Mex transporters, which can be exploited to optimize transport and inhibition propensities of antimicrobial compounds. Frontiers Media S.A. 2022-11-11 /pmc/articles/PMC9691783/ /pubmed/36438787 http://dx.doi.org/10.3389/fphar.2022.1021916 Text en Copyright © 2022 Catte, K. Ramaswamy, Vargiu, Malloci, Bosin and Ruggerone. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Pharmacology Catte, Andrea K. Ramaswamy, Venkata Vargiu, Attilio Vittorio Malloci, Giuliano Bosin, Andrea Ruggerone, Paolo Common recognition topology of mex transporters of Pseudomonas aeruginosa revealed by molecular modelling |
title | Common recognition topology of mex transporters of Pseudomonas aeruginosa revealed by molecular modelling |
title_full | Common recognition topology of mex transporters of Pseudomonas aeruginosa revealed by molecular modelling |
title_fullStr | Common recognition topology of mex transporters of Pseudomonas aeruginosa revealed by molecular modelling |
title_full_unstemmed | Common recognition topology of mex transporters of Pseudomonas aeruginosa revealed by molecular modelling |
title_short | Common recognition topology of mex transporters of Pseudomonas aeruginosa revealed by molecular modelling |
title_sort | common recognition topology of mex transporters of pseudomonas aeruginosa revealed by molecular modelling |
topic | Pharmacology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9691783/ https://www.ncbi.nlm.nih.gov/pubmed/36438787 http://dx.doi.org/10.3389/fphar.2022.1021916 |
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