Mechanism of inhibition of the human matrix metalloproteinase stromelysin-1 by TIMP-1.

摘要: Matrix metalloproteinases (MMPs) are zinc endopeptidases that required for the degradation of extracellular matrix components during normal embryo development, morphogenesis and tissue remodelling 1 . Their proteolytic activities precisely regulated by endogenous inhibitors (TIMPs) 1-5 Disruption this balance results in diseases such as arthritis, atherosclerosis, tumour growth metastasis 1,2 Here we report crystal structure an MMP-TIMP complex formed between catalytic domain human stromelysin-1 (MMP-3) TIMP-1. TIMP-1, a 184-residue protein 5 , has shape elongated, contiguous wedge. With its long edge, consisting five different chain regions, it occupies entire length active-site cleft MMP-3. The central disulphide-linked segments Cys 1-Thr 2-Cys 3-Val 4 Ser 68-Val 69 bind to either side zinc. I bidentally coordinates zinc, Thr-2 extends into large specificity pocket This unusual architecture interface MMP-3 TIMP-1 suggests new possibilities designing TIMP variants synthetic MMP with potential therapeutic applications.