Bussiere D E, Pratt S D, Katz L, Severin J M, Holzman T, Park C H
Laboratory of Protein Crystallography, Abbott Laboratories, Illinois 60064, USA.
Mol Cell. 1998 Jul;2(1):75-84. 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.
VanX是一种锌依赖性D-丙氨酰-D-丙氨酸二肽酶，是介导肠球菌中基于转座子的万古霉素抗性系统的关键组成部分。它也是规避临床万古霉素抗性的关键药物靶点。粪肠球菌VanX的结构已通过X射线晶体学解析，揭示了一种具有独特整体折叠和明确活性位点的Zn(2+)二肽酶，该活性位点位于有限大小的腔内。还以高分辨率展示了VanX、VanX:D-丙氨酰-D-丙氨酸复合物、VanX:D-丙氨酸复合物以及与膦酸酯和次膦酸酯过渡态类似物抑制剂复合的VanX的晶体结构。对已知结构的结构同源性搜索表明，VanX的折叠与两种蛋白质相似：小鼠音猬因子的N端片段和白色链霉菌G的Zn(2+)依赖性N-酰基-D-丙氨酰-D-丙氨酸羧肽酶。
