Structural basis for potent slow binding inhibition of human matrix metalloproteinase-2 (MMP-2)
Structural basis for potent slow binding inhibition of human matrix metalloproteinase-2 (MMP-2)
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DOI：
10.1074/jbc.m301139200
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发表时间：
2003-07-18
影响因子：
4.8
通讯作者：
Sagi, I
中科院分区：
文献类型：
--
作者：
Rosenblum, G;Meroueh, SO;Sagi, I
锌依赖性明胶酶属于基质金属蛋白酶 (MMP) 家族，该酶已被证明在血管生成和肿瘤转移中发挥关键作用。这些酶能够在生理条件下水解细胞外基质（ECM）成分。人们高度寻求旨在阻断其活性的特异性和选择性抑制剂作为潜在的治疗剂。我们在此报告了最近表征的抑制剂 4-(4-苯氧苯磺酰基)丁烷-1,2-二硫醇（抑制剂 1）和 5-(4-苯氧苯磺酰基）戊烷-1,2-二硫醇（抑制剂 2）抑制明胶酶 A (MMP-2) 的新模式。这些合成抑制剂对 MMP-2 和 MMP-9 有选择性。我们发现这些抑制剂的二硫醇部分通过两个硫原子螯合 MMP-2 的催化锌离子。这种结合模式导致金属离子配位数的改变，并在催化锌离子的微环境中诱导构象变化；一系列事件可能是这些抑制剂表现出的有效缓慢结合抑制行为的根源。这项研究展示了一种了解有效抑制剂和 MMP 催化位点之间分子相互作用的结构机制的独特方法，这可能有助于设计有效的抑制剂。
The zinc-dependent gelatinases belong to the family of matrix metalloproteinases ( MMPs), enzymes that have been shown to play a key role in angiogenesis and tumor metastasis. These enzymes are capable of hydrolyzing extracellular matrix (ECM) components under physiological conditions. Specific and selective inhibitors aimed at blocking their activity are highly sought for use as potential therapeutic agents. We report herein on a novel mode of inhibition of gelatinase A (MMP-2) by the recently characterized inhibitors 4-(4-phenoxphenylsulfonyl) butane-1,2-dithiol ( inhibitor 1) and 5-(4-phenoxphenylsulfonyl) pentane-1,2-dithiol ( inhibitor 2). These synthetic inhibitors are selective for MMP-2 and MMP-9. We show that the dithiolate moiety of these inhibitors chelates the catalytic zinc ion of MMP-2 via two sulfur atoms. This mode of binding results in alternation of the coordination number of the metal ion and the induction of conformational changes at the microenvironment of the catalytic zinc ion; a set of events that is likely to be at the root of the potent slow binding inhibition behavior exhibited by these inhibitors. This study demonstrates a distinct approach for the understanding of the structural mechanism governing the molecular interactions between potent inhibitors and catalytic sites of MMPs, which may aid in the design of effective inhibitors.