Structural insights into the catalytic domains of human matrix metalloprotease-2 and human matrix metalloprotease-9: Implications for substrate specificities

Structural information for the gelatinases A (MMP-2) and B (MMP-9), two members of the matrix metalloprotease (MMP) family of enzymes, has been elusive. For the first time, computational structures for the catalytic domains of MMP-2 and MMP-9 are reported herein using the program COMPOSER and the reported three-dimensional structures of the fibroblast collagenase (MMP-1), neutrophil collagenase (MMP-8) and stromelysin-1 (MMP-3). The details of the structures of the catalytic domains of gelatinases and interactions with the protein substrate are discussed. The first analysis of the extent of hydrophobicity of surfaces in the active sites of six MMPs (including the two gelatinases reported herein) is presented to provide distinction for substrate specificity among these metalloproteases. The information from the extent of hydrophobicity/hydrophilicity analysis and general topology for these MMPs was utilized in the proposal of a method for categorization of MMPs of known three-dimensional fold. These efforts provide the first information useful to experimentalists working on the biochemical properties of these important members of the MMP family of enzymes, and provide for an opportunity to compare and contrast structures of gelatinases, collagenases and stromelysins.