| The 23 matrix metalloproteinases (MMPs) in humans catalyze the turnover of all protein components of the extracellular matrix (ECM) and have important roles in tissue remodeling, wound healing, embryo implantation, cell migration and shedding of cell surface proteins. Excess MMP activities are associated with many diseases including arthritis, heart disease and cancer. The activities of MMPs are regulated by a family of four protein inhibitors, the tissue inhibitors of metalloproteinases (TIMPs), that are endogenous inhibitors of matrix metalloproteinases (MMPs), ADAMs (A Disintegrin And Metalloproteinase) and ADAMTS (disintegrin- metalloproteinases with thrombospmdin motifs). There are four human TIMPs (TIMP-1 to -4). These are two-domain molecules in which the N-terminal domain (N-TIMP) carries the MMP inhibitory activity. The balance between TIMPs and active metzincins is very important and imbalances are linked to human diseases such as arthritis, cancer, and atherosclerosis. The engineering of TIMPs to produce specific inhibitors of individual MPs could provide new therapeutic principles for disease treatment but this requires a detailed understanding of the biophysical and structural basis of the interactions of TIMPs with MMPs and ADAMs.;From the current studies it appears that the properties of the MMP may have a predominant influence in the thermodynamic profiles for the interactions of N-TIMP-1 and -2 with MMP-1 and -3. Although the binding site of MMP-3 is more hydrophobic than that of MMP-1, the heat capacity change is much lower for interactions with MMP-3, reflecting structural changes that accompany the interaction. With the mutants, it appears that the S2D/S4A mutant interacts well with MMP-1 because of the unique presence of an arginine in the S1' pocket of its interaction site whereas with MMP-3 and other MMPs, there is charge repulsion between Asp 2 and the MMP catalytic site Glu. Selectivity in the S2V mutant appears to be linked to a greater structural change induced by its interaction with MMP-3. |
