The Structure of VanX Reveals a Novel Amino-Dipeptidase Involved in Mediating Transposon-Based Vancomycin Resistance

• Published in: Molecular cell Vol. 2; no. 1; pp. 75 - 84
• Main Authors: Bussiere, Dirksen E., Pratt, Steven D., Katz, Leonard, Severin, Jean M., Holzman, Thomas, Park, Chang H.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-07-1998
• Subjects: Alanine - metabolism; Amino Acid Sequence; Animals; Bacterial Proteins - antagonists & inhibitors; Bacterial Proteins - chemistry; Binding Sites; Carboxypeptidases - chemistry; Copper - pharmacology; Crystallography, X-Ray; Dipeptidases - antagonists & inhibitors; Dipeptidases - chemistry; Dipeptides - metabolism; DNA Transposable Elements - genetics; Drug Resistance, Microbial - genetics; Enterococcus faecium; 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
• ISSN: 1097-2765; 1097-4164; 1097-4164
• DOI: 10.1016/S1097-2765(00)80115-X

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.