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  The Xenobiotic Extrusion Mechanism of the MATE Transporter NorM_PS from Pseudomonas stutzeri

Eisinger, M. L., Nie, L., Dörrbaum, A. R., Langer, J. D., & Michel, H. (2018). The Xenobiotic Extrusion Mechanism of the MATE Transporter NorM_PS from Pseudomonas stutzeri. Journal of Molecular Biology (London), 430(9), 1311-1323. doi:10.1016/j.jmb.2018.03.012.

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 Creators:
Eisinger, Martin Lorenz1, Author              
Nie, Laiyin1, 2, Author              
Dörrbaum, Aline Ricarda3, Author
Langer, Julian David1, Author              
Michel, Hartmut1, Author              
Affiliations:
1Department of Molecular Membrane Biology, Max Planck Institute of Biophysics, Max Planck Society, ou_2068290              
2Structural Genomics Consortium, University of Oxford, Oxford, United Kingdom, ou_persistent22              
3Synaptic Plasticity Department, Max Planck Institute for Brain Research, Max Planck Society, ou_2461710              

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Free keywords: HDX-MS; membrane protein; multidrug transporter; conformational change; MATE transporter
 Abstract: Multidrug resistance (MDR) in bacterial pathogens has become a severe threat to public health. Membrane transporters of the multidrug and toxic compound extrusion (MATE) family contribute critically to MDR, making them promising drug targets. Despite recent advances, structures in different conformations and the mechanistic details of their antiport cycle are still elusive. Here we studied NorM_PS, a representative MATE transporter from Pseudomonas stutzeri, using biochemical assays in combination with hydrogen/deuterium exchange-mass spectrometry. Our results confirm that the antiport is proton dependent and electroneutral with a stoichiometry of two protons per one doubly positively charged substrate. We investigated the conformational dynamics upon substrate binding, and our hydrogen/deuterium exchange-mass spectrometry analysis revealed an occlusion in the proposed binding site as well as a closure of the cytoplasmic cavity and formation of a periplasmic cavity. Together with the results of selected variants (D38N, D373N and Q376A), we propose a six-step rocker-switch model for NorM_PS, which also increases our understanding of related MATE transporters and may help to fight the burden of MDR.

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Language(s): eng - English
 Dates: 2018-01-052018-03-142018-03-162018-04-27
 Publication Status: Published in print
 Pages: 13
 Publishing info: -
 Table of Contents: -
 Rev. Type: Peer
 Identifiers: DOI: 10.1016/j.jmb.2018.03.012
 Degree: -

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Title: Journal of Molecular Biology (London)
  Other : J Mol Biol
Source Genre: Journal
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Publ. Info: London : Academic Press
Pages: - Volume / Issue: 430 (9) Sequence Number: - Start / End Page: 1311 - 1323 Identifier: ISSN: 0022-2836
CoNE: https://pure.mpg.de/cone/journals/resource/954922646042