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), tw o members of the matrix metalloprotease (MMP) family of enzymes, has b een elusive. For the first time, computational structures for the cata lytic domains of MMP-2 and MMP-9 are reported herein using the program COMPOSER and the reported three-dimensional structures of the fibrobl ast collagenase (MMP-1), neutrophil collagenase (MMP-8) and stromelysi n-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 th e active sites of six MMPs (including the two gelatinases reported her ein) is presented to provide distinction for substrate specificity amo ng these metalloproteases. The information from the extent of hydropho bicity/hydrophilicity analysis and general topology for these MMPs was utilized in the proposal of a method for categorization of MMPs of kn own three-dimensional fold. These efforts provide the first informatio n 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, coll agenases and stromelysins.