Gomis-Rüth F X, Maskos K, Betz M, Bergner A, Huber R, Suzuki K, Yoshida N, Nagase H, Brew K, Bourenkov G P, Bartunik H, Bode W
Max-Planck-Institut für Biochemie, Abteilung für Strukturforschung, Martinsried, Germany.
Nature. 1997 Sep 4;389(6646):77-81. doi: 10.1038/37995.
Matrix metalloproteinases (MMPs) are zinc endopeptidases that are required for the degradation of extracellular matrix components during normal embryo development, morphogenesis and tissue remodelling. Their proteolytic activities are precisely regulated by endogenous tissue inhibitors of metalloproteinases (TIMPs). Disruption of this balance results in diseases such as arthritis, atherosclerosis, tumour growth and metastasis. 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, 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.
基质金属蛋白酶（MMPs）是锌内肽酶，在正常胚胎发育、形态发生和组织重塑过程中，细胞外基质成分的降解需要它们。其蛋白水解活性受到金属蛋白酶组织抑制剂（TIMPs）的精确调控。这种平衡的破坏会导致诸如关节炎、动脉粥样硬化、肿瘤生长和转移等疾病。在此，我们报道了人基质溶解素-1（MMP-3）的催化结构域与人类TIMP-1之间形成的MMP-TIMP复合物的晶体结构。TIMP-1是一种由184个残基组成的蛋白质，呈细长连续楔形。它的长边由五个不同的链区域组成，占据了MMP-3活性位点裂隙的全长。中央二硫键连接的片段Cys 1-Thr 2-Cys 3-Val 4和Ser 68-Val 69与催化锌的两侧结合。Cys 1与该锌意外配位，Thr-2侧链延伸至MMP-3的大特异性口袋中。MMP-3与TIMP-1之间这种不同寻常的界面结构为设计具有潜在治疗应用的TIMP变体和合成MMP抑制剂提供了新的可能性。
