THE STRUCTURE OF VANX REVEALS A NOVEL AMINO-DIPEPTIDASE INVOLVED IN MEDIATING TRANSPOSON-BASED VANCOMYCIN RESISTANCE

VanX is a zinc-dependent D-alanyl-D-alanine dipeptidase that is a crit ical component in a system that mediates transposon-based vancomycin r esistance in enterococci. It is also a key drug target in circumventin g clinical vancomycin resistance. The structure of VanX from E. faeciu m has been solved by X-ray crystallography and reveals a Zn2+-dipeptid ase 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 in hibitors, are also presented at high resolution. Structural homology s earches of known structures revealed that the fold of VanX is similar to those of two proteins: the N-terminal fragment of murine Sonic hedg ehog and the Zn2+-dependent N-acyl-D-alanyl-D-alanine carboxypeptidase of S. albus G.