The 1.15 Å crystal structure of the Staphylococcus aureus methionyl-aminopeptidase and complexes with triazole based inhibitors
The 1.15 Å crystal structure of the Staphylococcus aureus methionyl-aminopeptidase and complexes with triazole based inhibitors
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DOI：
10.1016/s0022-2836(03)00862-3
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发表时间：
2003-09-05
影响因子：
5.6
通讯作者：
Dale, GE
中科院分区：
文献类型：
--
作者：
Oefner, C;Douangamath, A;Dale, GE
蛋氨酸氨基肽酶（Methionyl aminopeptidases, MetAPs）是一类独特的蛋白酶，负责从蛋白质和肽中去除n端蛋氨酸残基。这里描述了两个主要的metap类（类型I和类型II），每个类都可以细分为两个子类。真核生物同时含有I型和II型metap，而原核生物只含有I型metap。由于这些酶在生理上的重要性，有相当大的兴趣将抑制剂用作抗血管生成和抗菌剂。在这里，我们以高分辨率描述了金黄色葡萄球菌MetAP-1的1.15埃晶体结构，作为一种脱酶及其与各种1,2,4-三唑衍生物的配合物。与其他MetAP结构一样，该蛋白质具有典型的“皮塔面包”折叠。抑制剂在活性位点与三唑部分的N1和N2原子结合，使两个二价离子络合。1,2,4-三唑代表了一类新的有效的MetAP-Is非肽抑制剂。(C) 2003 Elsevier Ltd.版权所有。
Methionyl aminopeptidases (MetAPs) represent a unique class of protease that are responsible for removing the N-terminal methionine residue from proteins and peptides. There are two major classes of MetAPs (type I and type II) described and each class can be subdivided into two subclasses. Eukaryotes contain both the type I and type II MetAPs, whereas prokaryotes possess only the type I enzyme. Due to the physiological importance of these enzymes there is considerable interest in inhibitors to be used as antiangiogenic and antimicrobial agents. Here, we describe the 1.15 Angstrom crystal structure of the Staphylococcus aureus MetAP-1 as an apoenzyme and its complexes with various 1,2,4-triazole-based derivatives at high-resolution. The protein has a typical "pita-bread" fold as observed for the other MetAP structures. The inhibitors bind in the active site with the N1 and N2 atoms of the triazole moiety complexing two divalent ions. The 1,2,4-triazols represent a novel class of potent non-peptidic inhibitors for the MetAP-Is. (C) 2003 Elsevier Ltd. All rights reserved.