Vancomycin resistance: structure of D-alanine:D-alanine ligase at 2.3 A resolution

Science. 1994 Oct 21;266(5184):439-43. doi: 10.1126/science.7939684.

Abstract

The molecular structure of the D-alanine:D-alanine ligase of the ddlB gene of Escherichia coli, co-crystallized with an S,R-methylphosphinate and adenosine triphosphate, was determined by x-ray diffraction to a resolution of 2.3 angstroms. A catalytic mechanism for the ligation of two D-alanine substrates is proposed in which a helix dipole and a hydrogen-bonded triad of tyrosine, serine, and glutamic acid assist binding and deprotonation steps. From sequence comparison, it is proposed that a different triad exists in a recently discovered D-alanine:D-lactate ligase (VanA) present in vancomycin-resistant enterococci. A molecular mechanism for the altered specificity of VanA is suggested.

Publication types

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

MeSH terms

  • Adenosine Diphosphate / chemistry
  • Adenosine Diphosphate / metabolism
  • Amino Acid Sequence
  • Bacterial Proteins / chemistry
  • Binding Sites
  • Carbon-Oxygen Ligases*
  • Computer Graphics
  • Crystallography, X-Ray
  • Dipeptides / biosynthesis
  • Drug Resistance, Microbial
  • Escherichia coli / drug effects
  • Escherichia coli / enzymology*
  • Hydrogen Bonding
  • Ligases / chemistry
  • Models, Molecular
  • Molecular Sequence Data
  • Molecular Structure
  • Peptide Synthases / chemistry*
  • Peptide Synthases / genetics
  • Peptide Synthases / metabolism
  • Protein Structure, Secondary
  • Protein Structure, Tertiary
  • Substrate Specificity
  • Vancomycin / pharmacology*

Substances

  • Bacterial Proteins
  • Dipeptides
  • VanA ligase, Bacteria
  • alanylalanine
  • Adenosine Diphosphate
  • Vancomycin
  • Ligases
  • Carbon-Oxygen Ligases
  • Peptide Synthases
  • D-alanylalanine synthetase