Molecular mechanisms of HipA-mediated multidrug tolerance and its neutralization by HipB

Science. 2009 Jan 16;323(5912):396-401. doi: 10.1126/science.1163806.

Abstract

Bacterial multidrug tolerance is largely responsible for the inability of antibiotics to eradicate infections and is caused by a small population of dormant bacteria called persisters. HipA is a critical Escherichia coli persistence factor that is normally neutralized by HipB, a transcription repressor, which also regulates hipBA expression. Here, we report multiple structures of HipA and a HipA-HipB-DNA complex. HipA has a eukaryotic serine/threonine kinase-like fold and can phosphorylate the translation factor EF-Tu, suggesting a persistence mechanism via cell stasis. The HipA-HipB-DNA structure reveals the HipB-operator binding mechanism, approximately 70 degrees DNA bending, and unexpected HipA-DNA contacts. Dimeric HipB interacts with two HipA molecules to inhibit its kinase activity through sequestration and conformational inactivation. Combined, these studies suggest mechanisms for HipA-mediated persistence and its neutralization by HipB.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphate / metabolism
  • Crystallization
  • Crystallography, X-Ray
  • DNA, Bacterial / chemistry
  • DNA, Bacterial / metabolism
  • DNA-Binding Proteins / chemistry
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Dimerization
  • Drug Tolerance*
  • Escherichia coli / chemistry
  • Escherichia coli / drug effects*
  • Escherichia coli / genetics
  • Escherichia coli / metabolism*
  • Escherichia coli Proteins / antagonists & inhibitors
  • Escherichia coli Proteins / chemistry
  • Escherichia coli Proteins / genetics
  • Escherichia coli Proteins / metabolism*
  • Models, Molecular
  • Nucleic Acid Conformation
  • Operator Regions, Genetic
  • Operon
  • Peptide Elongation Factor Tu / metabolism
  • Phosphorylation
  • Protein Conformation
  • Protein Folding
  • Protein Kinase Inhibitors / metabolism
  • Protein Kinases / chemistry
  • Protein Kinases / metabolism
  • Protein Structure, Secondary
  • Protein Structure, Tertiary

Substances

  • DNA, Bacterial
  • DNA-Binding Proteins
  • Escherichia coli Proteins
  • Protein Kinase Inhibitors
  • hipB protein, E coli
  • hipA protein, E coli
  • Adenosine Triphosphate
  • Protein Kinases
  • Peptide Elongation Factor Tu

Associated data

  • PDB/3DNT
  • PDB/3DNU
  • PDB/3DNV
  • PDB/3DNW