Drug Export Pathway of Multidrug Exporter AcrB Revealed by DARPin Inhibitors

PLoS Biol. 2007 Jan;5(1):e7. doi: 10.1371/journal.pbio.0050007.

Abstract

The multidrug exporter AcrB is the inner membrane component of the AcrAB-TolC drug efflux system in Escherichia coli and is responsible for the resistance of this organism to a wide range of drugs. Here we describe the crystal structure of the trimeric AcrB in complex with a designed ankyrin-repeat protein (DARPin) inhibitor at 2.5-A resolution. The three subunits of AcrB are locked in different conformations revealing distinct channels in each subunit. There seems to be remote conformational coupling between the channel access, exit, and the putative proton-translocation site, explaining how the proton motive force is used for drug export. Thus our structure suggests a transport pathway not through the central pore but through the identified channels in the individual subunits, which greatly advances our understanding of the multidrug export mechanism.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Ankyrin Repeat / physiology*
  • Biological Transport / physiology
  • Crystallography, X-Ray
  • Drug Resistance, Multiple, Bacterial / physiology
  • Escherichia coli Proteins / antagonists & inhibitors
  • Escherichia coli Proteins / chemistry*
  • Escherichia coli Proteins / metabolism*
  • Multidrug Resistance-Associated Proteins / antagonists & inhibitors
  • Multidrug Resistance-Associated Proteins / chemistry*
  • Multidrug Resistance-Associated Proteins / metabolism*
  • Multiprotein Complexes / antagonists & inhibitors
  • Multiprotein Complexes / chemistry
  • Multiprotein Complexes / metabolism
  • Protein Binding / physiology
  • Protein Conformation
  • Protein Folding
  • Protein Subunits / antagonists & inhibitors
  • Protein Subunits / chemistry
  • Protein Subunits / metabolism
  • Proton-Motive Force / physiology
  • Signal Transduction / physiology*

Substances

  • AcrB protein, E coli
  • Escherichia coli Proteins
  • Multidrug Resistance-Associated Proteins
  • Multiprotein Complexes
  • Protein Subunits

Associated data

  • PDB/2J8S