Mechanism of inhibition of the human matrix metalloproteinase stromelysin-1 by TIMP-1
Mechanism of inhibition of the human matrix metalloproteinase stromelysin-1 by TIMP-1
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作者：
GomisRuth, FX;Maskos, K;Bode, W
基质金属蛋白酶（MMP）是锌内肽酶，在正常胚胎发育、形态发生和组织重塑过程中降解细胞外基质成分所需（1）。它们的蛋白水解活性受到内源性金属蛋白酶组织抑制剂（TIMP）的精确调节（1-5）。这种平衡的破坏导致疾病，如关节炎，动脉粥样硬化，肿瘤生长和转移（1，2）。在这里，我们报告的MMP-TIMP复合物之间形成的催化结构域的人基质分解素-1（MMP-3）和人TIMP-1的晶体结构。TIMP-1是一种184个残基的蛋白质（5），具有细长的连续楔形形状。它的长边由五个不同的链区组成，占据了MMP-3活性位点裂缝的整个长度。中心二硫键连接的区段Cys 1-Thr 2-Cys 3-瓦尔4和Ser 68-瓦尔69结合至催化锌的任一侧。Cys 1与该锌双向配位，Thr-2侧链延伸到MMP-3的大特异性口袋中。MMP-3和TIMP-1之间的界面的这种不寻常的结构提示了设计具有潜在治疗应用的TIMP变体和合成MMP抑制剂的新可能性。
Matrix metalloproteinases (MMPs) are zinc endopeptidases that are required for the degradation of extracellular matrix components during normal embryo development, morphogenesis and tissue remodelling(1). Their proteolytic activities are precisely regulated by endogenous tissue inhibitors of metalloproteinases (TIMPs)(1-5). Disruption of this balance results in diseases such as arthritis, atherosclerosis, tumour growth and metastasis(1,2). Here we report the crystal structure of an MMP-TIMP complex formed between the catalytic domain of human stromelysin-1 (MMP-3) and human TIMP-1. TIMP-1, a 184-residue protein(5), has the shape of an elongated, contiguous wedge. With its long edge, consisting of five different chain regions, it occupies the entire length of the active-site cleft of MMP-3. The central disulphide-linked segments Cys 1-Thr 2-Cys 3-Val 4 and Ser 68-Val 69 bind to either side of the catalytic zinc. Cys 1 bidentally coordinates this zinc, and the Thr-2 side chain extends into the large specificity pocket of MMP-3. This unusual architecture of the interface between MMP-3 and TIMP-1 suggests new possibilities for designing TIMP variants and synthetic MMP inhibitors with potential therapeutic applications.