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 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.
Bussiere
D E
DE
Laboratory of Protein Crystallography, Abbott Laboratories, Illinois 60064, USA. bussierd@tvsfrank.pprd.abbott.com
Pratt
S D
SD
Katz
L
L
Severin
J M
JM
Holzman
T
T
Park
C H
CH
D000409:Alanine / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry*; D001665:Binding Sites; D002268:Carboxypeptidases / Q000737:chemistry; D003300:Copper / Q000494:pharmacology; D018360:Crystallography, X-Ray; D004251:DNA Transposable Elements / Q000235:genetics*; D004150:Dipeptidases / Q000037:antagonists & inhibitors / Q000737:chemistry*; D004151:Dipeptides / Q000378:metabolism; D004352:Drug Resistance, Microbial / Q000235:genetics; D016984:Enterococcus faecium / Q000201:enzymology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D053823:Hedgehog Proteins; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009943:Organophosphorus Compounds / Q000494:pharmacology; D011422:Propionates / Q000494:pharmacology; D011487:Protein Conformation; D011506:Proteins / Q000737:chemistry; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D046929:Serine-Type D-Ala-D-Ala Carboxypeptidase; D013329:Structure-Activity Relationship; D015534:Trans-Activators; D014640:Vancomycin / Q000494:pharmacology*
C097170:3-((1-aminoethyl)phosphinyl)-2-methylpropionic acid; D001426:Bacterial Proteins; D004251:DNA Transposable Elements; D004151:Dipeptides; D004791:Enzyme Inhibitors; D053823:Hedgehog Proteins; D009943:Organophosphorus Compounds; D011422:Propionates; D011506:Proteins; D015534:Trans-Activators; C002956:alanylalanine; D014640:Vancomycin; D003300:Copper; D002268:Carboxypeptidases; D004150:Dipeptidases; D046929:Serine-Type D-Ala-D-Ala Carboxypeptidase; C091956:VanX dipeptidase; C033455:zinc D-Ala-D-Ala carboxypeptidase; D000409:Alanine; C029892:cupric chloride