The structure of VanX reveals a novel amino-dipeptidase involved in mediating transposon-based vancomycin resistance

Mol Cell. 1998 Jul;2(1):75-84. doi: 10.1016/s1097-2765(00)80115-x.

Abstract

VanX is a zinc-dependent D-alanyl-D-alanine dipeptidase that is a critical component in a system that mediates transposon-based vancomycin resistance in enterococci. It is also a key drug target in circumventing clinical vancomycin resistance. The structure of VanX from E. faecium has been solved by X-ray crystallography and reveals a Zn(2+)-dipeptidase with a unique overall fold and a well-defined active site confined within a cavity of limited size. The crystal structures of VanX, the VanX:D-alanyl-D-alanine complex, the VanX:D-alanine complex, and VanX in complex with phosphonate and phosphinate transition-state analog inhibitors, are also presented at high resolution. Structural homology searches of known structures revealed that the fold of VanX is similar to those of two proteins: the N-terminal fragment of murine Sonic hedgehog and the Zn(2+)-dependent N-acyl-D-alanyl-D-alanine carboxypeptidase of S. albus G.

Publication types

  • Comparative Study

MeSH terms

  • Alanine / metabolism
  • Amino Acid Sequence
  • Animals
  • Bacterial Proteins / antagonists & inhibitors
  • Bacterial Proteins / chemistry*
  • Binding Sites
  • Carboxypeptidases / chemistry
  • Copper / pharmacology
  • Crystallography, X-Ray
  • DNA Transposable Elements / genetics*
  • Dipeptidases / antagonists & inhibitors
  • Dipeptidases / chemistry*
  • Dipeptides / metabolism
  • Drug Resistance, Microbial* / genetics
  • Enterococcus faecium / enzymology*
  • Enzyme Inhibitors / pharmacology
  • Hedgehog Proteins
  • Mice
  • Models, Molecular
  • Molecular Sequence Data
  • Organophosphorus Compounds / pharmacology
  • Propionates / pharmacology
  • Protein Conformation*
  • Proteins / chemistry
  • Sequence Alignment
  • Sequence Homology, Amino Acid
  • Serine-Type D-Ala-D-Ala Carboxypeptidase*
  • Structure-Activity Relationship
  • Trans-Activators*
  • Vancomycin / pharmacology*

Substances

  • 3-((1-aminoethyl)phosphinyl)-2-methylpropionic acid
  • Bacterial Proteins
  • DNA Transposable Elements
  • Dipeptides
  • Enzyme Inhibitors
  • Hedgehog Proteins
  • Organophosphorus Compounds
  • Propionates
  • Proteins
  • Trans-Activators
  • alanylalanine
  • Vancomycin
  • Copper
  • Carboxypeptidases
  • Dipeptidases
  • Serine-Type D-Ala-D-Ala Carboxypeptidase
  • VanX dipeptidase
  • zinc D-Ala-D-Ala carboxypeptidase
  • Alanine
  • cupric chloride