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

Eisinger, Martin Lorenz; Nie, Laiyin; Dörrbaum, Aline Ricarda; Langer, Julian David; Michel, Hartmut

doi:10.1016/j.jmb.2018.03.012

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

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Eisinger, Martin Lorenz
Department of Molecular Membrane Biology, Max Planck Institute of Biophysics, Max Planck Society;

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Nie, Laiyin
Department of Molecular Membrane Biology, Max Planck Institute of Biophysics, Max Planck Society;
Structural Genomics Consortium, University of Oxford, Oxford, United Kingdom;

Dörrbaum, Aline Ricarda
Synaptic Plasticity Department, Max Planck Institute for Brain Research, Max Planck Society;

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Langer, Julian David
Department of Molecular Membrane Biology, Max Planck Institute of Biophysics, Max Planck Society;

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Michel, Hartmut
Department of Molecular Membrane Biology, Max Planck Institute of Biophysics, Max Planck Society;

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Citation

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.

Cite as: https://hdl.handle.net/21.11116/0000-0002-64E8-8

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.