Structural basis of multiple drug-binding capacity of the AcrB multidrug efflux pump

Science. 2003 May 9;300(5621):976-80. doi: 10.1126/science.1083137.

Abstract

Multidrug efflux pumps cause serious problems in cancer chemotherapy and treatment of bacterial infections. Yet high-resolution structures of ligand transporter complexes have previously been unavailable. We obtained x-ray crystallographic structures of the trimeric AcrB pump from Escherichia coli with four structurally diverse ligands. The structures show that three molecules of ligands bind simultaneously to the extremely large central cavity of 5000 cubic angstroms, primarily by hydrophobic, aromatic stacking and van der Waals interactions. Each ligand uses a slightly different subset of AcrB residues for binding. The bound ligand molecules often interact with each other, stabilizing the binding.

Publication types

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

MeSH terms

  • Anti-Infective Agents / chemistry
  • Anti-Infective Agents / metabolism
  • Anti-Infective Agents, Local / chemistry
  • Anti-Infective Agents, Local / metabolism
  • Binding Sites
  • Carrier Proteins / chemistry*
  • Carrier Proteins / isolation & purification
  • Carrier Proteins / metabolism*
  • Cell Membrane / chemistry
  • Chemical Phenomena
  • Chemistry, Physical
  • Ciprofloxacin / chemistry
  • Ciprofloxacin / metabolism
  • Crystallization
  • Crystallography, X-Ray
  • Dequalinium / chemistry
  • Dequalinium / metabolism
  • Escherichia coli Proteins / chemistry*
  • Escherichia coli Proteins / isolation & purification
  • Escherichia coli Proteins / metabolism*
  • Ethidium / chemistry
  • Ethidium / metabolism
  • Hydrogen Bonding
  • Hydrophobic and Hydrophilic Interactions
  • Ligands
  • Membrane Proteins / chemistry*
  • Membrane Proteins / isolation & purification
  • Membrane Proteins / metabolism*
  • Models, Molecular
  • Multidrug Resistance-Associated Proteins
  • Protein Binding
  • Protein Conformation
  • Protein Structure, Quaternary
  • Protein Structure, Secondary
  • Protein Structure, Tertiary
  • Rhodamines / chemistry
  • Rhodamines / metabolism
  • Static Electricity

Substances

  • AcrB protein, E coli
  • Anti-Infective Agents
  • Anti-Infective Agents, Local
  • Carrier Proteins
  • Escherichia coli Proteins
  • Ligands
  • Membrane Proteins
  • Multidrug Resistance-Associated Proteins
  • Rhodamines
  • Ciprofloxacin
  • Dequalinium
  • Ethidium

Associated data

  • PDB/1OY6
  • PDB/1OY8
  • PDB/1OY9
  • PDB/1OYD
  • PDB/1OYE