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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

Flexibility in a drug transport accessory protein: molecular dynamics simulations of MexA

Loredana Vaccaro1, Vassilis Koronakis, Mark S P Sansom

  • 1Department of Biochemistry, University of Oxford, Oxford OX1 3QU, United Kingdom.

Biophysical Journal
|May 2, 2006
PubMed

Insights

Molecular dynamics simulations reveal that the Pseudomonas aeruginosa adaptor protein MexA exhibits significant interdomain flexibility. This flexibility, characterized by hinge-bending and rotation, is crucial for its role in the tripartite efflux pump complex.

Area of Science:

  • Microbiology and Molecular Biology
  • Structural Biology
  • Biochemistry

Background:

  • Gram-negative bacteria utilize tripartite efflux pumps, comprising an inner membrane pump, outer membrane pore, and periplasmic adaptor protein, to confer drug resistance.
  • In Escherichia coli, these components are AcrB, TolC, and AcrA; in Pseudomonas aeruginosa, they are MexB, OprM, and MexA, respectively.
  • Understanding the dynamics of the adaptor protein is key to elucidating the mechanism of efflux complex formation and function.

Purpose of the Study:

  • To define the interdomain dynamics of the Pseudomonas aeruginosa adaptor protein, MexA.
  • To elucidate how MexA's conformational flexibility contributes to its function within the tripartite efflux pump complex.

Main Methods:

  • Performed extended (25 nanoseconds) molecular dynamics simulations of the MexA protein.
  • Analyzed conformational drift to identify relative domain motions.
  • Utilized principal components analysis to determine dominant motional modes.

Main Results:

  • Demonstrated substantial motions between the three domains of MexA.
  • Identified a dominant hinge-bending motion.
  • Revealed a significant rotation of the alpha-helical hairpin relative to other domains as a key dynamic feature.

Conclusions:

  • MexA exhibits considerable interdomain flexibility through hinge-bending and rotational motions.
  • This inherent flexibility is likely essential for MexA's adaptor function in assembling and operating the tripartite efflux pump.
  • The findings provide insights into the structural basis of drug resistance mechanisms in Pseudomonas aeruginosa.

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