Molecular Rationale behind the Differential Substrate Specificity of Bacterial RND Multi-Drug Transporters
Abstract Resistance-Nodulation-cell Division (RND) transporters AcrB and AcrD of Escherichia coli expel a wide range of substrates out of the cell in conjunction with AcrA and TolC, contributing to the onset of bacterial multidrug resistance. Despite sharing an overall sequence identity of ~66% (sim...
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doaj-392930ee1eca422298bd285496cace512020-12-08T02:56:01ZengNature Publishing GroupScientific Reports2045-23222017-08-017111810.1038/s41598-017-08747-8Molecular Rationale behind the Differential Substrate Specificity of Bacterial RND Multi-Drug TransportersVenkata Krishnan Ramaswamy0Attilio V. Vargiu1Giuliano Malloci2Jürg Dreier3Paolo Ruggerone4Department of Physics, University of Cagliari, Cittadella UniversitariaDepartment of Physics, University of Cagliari, Cittadella UniversitariaDepartment of Physics, University of Cagliari, Cittadella UniversitariaBasilea Pharmaceutica International Ltd.Department of Physics, University of Cagliari, Cittadella UniversitariaAbstract Resistance-Nodulation-cell Division (RND) transporters AcrB and AcrD of Escherichia coli expel a wide range of substrates out of the cell in conjunction with AcrA and TolC, contributing to the onset of bacterial multidrug resistance. Despite sharing an overall sequence identity of ~66% (similarity ~80%), these RND transporters feature distinct substrate specificity patterns whose underlying basis remains elusive. We performed exhaustive comparative analyses of the putative substrate binding pockets considering crystal structures, homology models and conformations extracted from multi-copy μs-long molecular dynamics simulations of both AcrB and AcrD. The impact of physicochemical and topographical properties (volume, shape, lipophilicity, electrostatic potential, hydration and distribution of multi-functional sites) within the pockets on their substrate specificities was quantitatively assessed. Differences in the lipophilic and electrostatic potentials among the pockets were identified. In particular, the deep pocket of AcrB showed the largest lipophilicity convincingly pointing out its possible role as a lipophilicity-based selectivity filter. Furthermore, we identified dynamic features (not inferable from sequence analysis or static structures) such as different flexibilities of specific protein loops that could potentially influence the substrate recognition and transport profile. Our findings can be valuable for drawing structure (dynamics)-activity relationship to be employed in drug design.https://doi.org/10.1038/s41598-017-08747-8 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Venkata Krishnan Ramaswamy Attilio V. Vargiu Giuliano Malloci Jürg Dreier Paolo Ruggerone |
spellingShingle |
Venkata Krishnan Ramaswamy Attilio V. Vargiu Giuliano Malloci Jürg Dreier Paolo Ruggerone Molecular Rationale behind the Differential Substrate Specificity of Bacterial RND Multi-Drug Transporters Scientific Reports |
author_facet |
Venkata Krishnan Ramaswamy Attilio V. Vargiu Giuliano Malloci Jürg Dreier Paolo Ruggerone |
author_sort |
Venkata Krishnan Ramaswamy |
title |
Molecular Rationale behind the Differential Substrate Specificity of Bacterial RND Multi-Drug Transporters |
title_short |
Molecular Rationale behind the Differential Substrate Specificity of Bacterial RND Multi-Drug Transporters |
title_full |
Molecular Rationale behind the Differential Substrate Specificity of Bacterial RND Multi-Drug Transporters |
title_fullStr |
Molecular Rationale behind the Differential Substrate Specificity of Bacterial RND Multi-Drug Transporters |
title_full_unstemmed |
Molecular Rationale behind the Differential Substrate Specificity of Bacterial RND Multi-Drug Transporters |
title_sort |
molecular rationale behind the differential substrate specificity of bacterial rnd multi-drug transporters |
publisher |
Nature Publishing Group |
series |
Scientific Reports |
issn |
2045-2322 |
publishDate |
2017-08-01 |
description |
Abstract Resistance-Nodulation-cell Division (RND) transporters AcrB and AcrD of Escherichia coli expel a wide range of substrates out of the cell in conjunction with AcrA and TolC, contributing to the onset of bacterial multidrug resistance. Despite sharing an overall sequence identity of ~66% (similarity ~80%), these RND transporters feature distinct substrate specificity patterns whose underlying basis remains elusive. We performed exhaustive comparative analyses of the putative substrate binding pockets considering crystal structures, homology models and conformations extracted from multi-copy μs-long molecular dynamics simulations of both AcrB and AcrD. The impact of physicochemical and topographical properties (volume, shape, lipophilicity, electrostatic potential, hydration and distribution of multi-functional sites) within the pockets on their substrate specificities was quantitatively assessed. Differences in the lipophilic and electrostatic potentials among the pockets were identified. In particular, the deep pocket of AcrB showed the largest lipophilicity convincingly pointing out its possible role as a lipophilicity-based selectivity filter. Furthermore, we identified dynamic features (not inferable from sequence analysis or static structures) such as different flexibilities of specific protein loops that could potentially influence the substrate recognition and transport profile. Our findings can be valuable for drawing structure (dynamics)-activity relationship to be employed in drug design. |
url |
https://doi.org/10.1038/s41598-017-08747-8 |
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