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Apr 22, 2011;18 (4): 454-63.

Sequential mechanism of assembly of multidrug efflux pump AcrAB-TolC.

Elena B Tikhonova, Yoichi Yamada, Helen I Zgurskaya
Author Information
  1. Elena B Tikhonova: Department of Chemistry and Biochemistry, Stephenson Life Science Research Center, University of Oklahoma, Norman, OK 73019, USA.
PMID: 21513882 DOI: 10.1016/j.chembiol.2011.02.011

Abstract

Multidrug efflux pumps adversely affect both the clinical effectiveness of existing antibiotics and the discovery process to find new ones. In this study, we reconstituted and characterized by surface plasmon resonance the assembly of AcrAB-TolC, the archetypal multidrug efflux pump from Escherichia coli. We report that the periplasmic AcrA and the outer membrane channel TolC assemble high-affinity complexes with AcrB transporter independently from each other. Antibiotic novobiocin and MC-207,110 inhibitor bind to the immobilized AcrB but do not affect interactions between components of the complex. In contrast, DARPin inhibits interactions between AcrA and AcrB. Mutational opening of TolC channel decreases stability of interactions and promotes disassembly of the complex. The conformation of the membrane proximal domain of AcrA is critical for the formation of AcrAB-TolC and could be targeted for the development of new inhibitors.

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Grants

  1. R01 AI052293/NIAID NIH HHS
  2. R01 AI052293-09/NIAID NIH HHS
  3. R56 AI052293/NIAID NIH HHS
  4. AI052293/NIAID NIH HHS

MeSH Term

Bacterial Outer Membrane Proteins
Escherichia coli
Escherichia coli Proteins
Immobilized Proteins
Lipid Metabolism
Lipoproteins
Membrane Transport Proteins
Models, Molecular
Multidrug Resistance-Associated Proteins
Mutation
Protein Binding
Protein Conformation
Surface Plasmon Resonance

Chemicals

AcrA protein, E coli
AcrB protein, E coli
Bacterial Outer Membrane Proteins
Escherichia coli Proteins
Immobilized Proteins
Lipoproteins
Membrane Transport Proteins
Multidrug Resistance-Associated Proteins
tolC protein, E coli
Journal Article Research Support, N.I.H., Extramural

Word Cloud

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