Modeling the tripartite drug efflux pump archetype: structural and functional studies of the macromolecular constituents reveal more than their names imply

J Chemother. 2005 Dec;17(6):581-92. doi: 10.1179/joc.2005.17.6.581.

Abstract

It is a remarkable age in molecular biology when one can argue that our current understanding of a process is influenced as much by structural studies as it is by genetic and physiological manipulations. This statement is particularly poignant with membrane proteins for which structural knowledge has been long impeded by the inability to easily obtain crystal structures in a lipid matrix. Thus, several high-resolution structures of the components comprising tripartite multidrug efflux pumps from Escherichia coli and Pseudomonas aeruginosa are now available and were received with much acclaim over ever-evolving crystal structures of soluble, aqueous proteins. These structures, in conjunction with functional mutagenesis studies, have provided insight into substrate capture and binding domains and redefined the potential interactions between individual pump constituents. However, correct assembly of the components is still a matter of debate as is the functional contribution of each to the translocation of drug substrates over long distances spanning the Gram-negative cell envelope.

Publication types

  • Research Support, U.S. Gov't, P.H.S.
  • Review

MeSH terms

  • Bacterial Outer Membrane Proteins / chemistry*
  • Bacterial Outer Membrane Proteins / physiology
  • Biological Transport, Active
  • Carrier Proteins / chemistry*
  • Carrier Proteins / physiology
  • Drug Resistance, Multiple, Bacterial
  • Escherichia coli / metabolism
  • Escherichia coli Proteins / chemistry*
  • Escherichia coli Proteins / physiology
  • Gram-Negative Bacteria / metabolism*
  • Lipoproteins / chemistry*
  • Lipoproteins / physiology
  • Membrane Fusion Proteins / metabolism
  • Membrane Proteins / chemistry*
  • Membrane Proteins / physiology
  • Membrane Transport Proteins
  • Models, Biological
  • Models, Molecular
  • Multidrug Resistance-Associated Proteins
  • Protein Conformation
  • Pseudomonas aeruginosa / metabolism

Substances

  • AcrA protein, E coli
  • AcrB protein, E coli
  • Bacterial Outer Membrane Proteins
  • Carrier Proteins
  • Escherichia coli Proteins
  • Lipoproteins
  • Membrane Fusion Proteins
  • Membrane Proteins
  • Membrane Transport Proteins
  • Multidrug Resistance-Associated Proteins
  • tolC protein, E coli