Crystal Structure of DIM-1, an Acquired Subclass B1 Metallo-β-Lactamase from Pseudomonas stutzeri.
Crystal Structure of DIM-1, an Acquired Subclass B1 Metallo-β-Lactamase from Pseudomonas stutzeri.
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DOI：
10.1371/journal.pone.0140059
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Spencer J
中科院分区：
文献类型：
--
作者：
Booth MP;Kosmopoulou M;Poirel L;Nordmann P;Spencer J
金属-β-内酰胺酶(MBLS)能降解几乎所有类别的β-内酰胺类抗生素，包括碳青霉烯类--目前治疗革兰氏阴性细菌致病菌机会性感染的首选药物。MBL抑制剂的开发由于这一组酶的多样性以及新酶的出现而变得复杂，这些新酶继续被鉴定为染色体基因和可移动的遗传元件。其中一种新发现的MBL是DIM-1，一种可移动的酶，最初在机会性病原体Stutzeri中发现，但后来在其他物种和地点发现。DIM-1是一个B1MBL亚类，与TMB-1、GIM-1和IMP酶的关系比与VIM和NDM等临床上遇到的MBL更近，并且在推测的底物结合位点的224位具有Arg而不是更常见的Lys。本文报道了DIM-1的结晶和结构测定。DIM-1具有双核金属中心，在结晶学不对称单元的两个分子中观察到5(而不是更常见的4)配位的三组氨酸(Zn1)中心和4-和5-配位的Cys-His-Asp-(Zn2)中心。这些数据表明DIM-1活性部位的金属配位几何构型存在一定程度的可变性，并有助于将DIM-1纳入基于结构的MBL抑制剂发现计划。
Metallo-β-lactamases (MBLs) hydrolyze almost all classes of β-lactam antibiotic, including carbapenems—currently first choice drugs for opportunistic infections by Gram-negative bacterial pathogens. MBL inhibitor development is complicated by the diversity within this group of enzymes, and by the appearance of new enzymes that continue to be identified both as chromosomal genes and on mobile genetic elements. One such newly discovered MBL is DIM-1, a mobile enzyme originally discovered in the opportunist pathogen Pseudomonas stutzeri but subsequently identified in other species and locations. DIM-1 is a subclass B1 MBL more closely related to the TMB-1, GIM-1 and IMP enzymes than to other clinically encountered MBLs such as VIM and NDM; and possesses Arg, rather than the more usual Lys, at position 224 in the putative substrate binding site. Here we report the crystallization and structure determination of DIM-1. DIM-1 possesses a binuclear metal center with a 5 (rather than the more usual 4) co-ordinate tri-histidine (Zn1) site and both 4- and 5-co-ordinate Cys-His-Asp- (Zn2) sites observed in the two molecules of the crystallographic asymmetric unit. These data indicate a degree of variability in metal co-ordination geometry in the DIM-1 active site, as well as facilitating inclusion of DIM-1 in structure-based MBL inhibitor discovery programmes.