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In vitro Investigation of the MexAB Efflux Pump From Pseudomonas aeruginosa
13:40

In vitro Investigation of the MexAB Efflux Pump From Pseudomonas aeruginosa

Published on: February 17, 2014

The crystal structure of MexR from Pseudomonas aeruginosa in complex with its antirepressor ArmR

Mark S Wilke1, Markus Heller, A Louise Creagh

  • 1Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, BC, Canada V6T1Z3.

Proceedings of the National Academy of Sciences of the United States of America
|September 25, 2008
PubMed

Insights

The antirepressor peptide ArmR binds to the MexR repressor in Pseudomonas aeruginosa, preventing DNA binding and increasing multidrug resistance. This structural study reveals how ArmR allosterically regulates gene expression.

Area of Science:

  • Microbiology
  • Structural Biology
  • Biochemistry

Background:

  • Pseudomonas aeruginosa exhibits intrinsic antimicrobial resistance, exacerbated by multidrug efflux pumps like MexAB-OprM.
  • The mexAB-oprM operon is primarily regulated by the MarR family repressor MexR.
  • NalC repressor controls ArmR, an antirepressor peptide, which is hypothesized to allosterically inhibit MexR DNA binding.

Purpose of the Study:

  • To elucidate the structural mechanism by which the antirepressor peptide ArmR modulates the MexR repressor.
  • To determine the specific region of ArmR responsible for MexR binding.
  • To understand how this interaction impacts the regulation of multidrug resistance genes in Pseudomonas aeruginosa.

Main Methods:

  • Crystallography was used to solve the structure of MexR in complex with a C-terminal fragment of ArmR at 1.8 A resolution.
  • Structural analysis focused on identifying the MexR-binding region of ArmR and the interaction interface.
  • Comparison of the MexR-ArmR complex structure with apo-MexR structure was performed.

Main Results:

  • The C-terminal 25 residues of ArmR bind to a central, hydrophobic cavity within the MexR dimer.
  • ArmR forms a kinked alpha-helix that occupies this binding site.
  • The ArmR-bound MexR undergoes a conformational change that prevents DNA binding, indicating allosteric derepression.

Conclusions:

  • This study defines the structural basis for ArmR-mediated allosteric regulation of MexR.
  • The findings reveal how ArmR binding induces a conformational change in MexR, inhibiting its DNA-binding capacity.
  • This work provides critical insights into the regulation of multidrug resistance in Pseudomonas aeruginosa.

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