X-ray structure of a novel matrix metalloproteinase inhibitor complexed tostromelysin

A new class of matrix metalloproteinase (MMP) inhibitors has been identifie d by screening a collection of compounds against stromelysin. The inhibitor s, 2,4,6-pyrimidine triones, have proven to be potent inhibitors of gelatin ases A and B. An X-ray crystal structure of one representative compound bou nd to the catalytic domain of stromelysin shows that the compounds bind at the active site and Ligand the active-site zinc. The pyrimidine triones mim ic substrates in forming hydrogen bonds to key residues in the active site, and provide opportunities for placing appropriately chosen groups into the S1' specificity pocket of MMPs. A number of compounds have been synthesize d and assayed against stromelysin, and the variations in potency are explai ned in terms of the binding mode revealed in the X-ray crystal structure.