X‐ray structure of a novel matrix metalloproteinase inhibitor complexed to stromelysin

• Published in: Protein science 2001-05, Vol.10 (5), p.923-926
• Main Authors: Dunten, Pete, Kammlott, Ursula, Crowther, Robert, Levin, Wayne, Foley, Louise H., Wang, Ping, Palermo, Robert
• Format: Article
• Language: English
• Subjects: Binding Sites; Crystallography, X-Ray; Hydrogen Bonding; Inhibitory Concentration 50; Matrix Metalloproteinase 3 - chemistry; Matrix Metalloproteinase 3 - metabolism; Matrix Metalloproteinase Inhibitors; MMP; Models, Molecular; protease inhibitor; Protease Inhibitors - chemical synthesis; Protease Inhibitors - chemistry; Protease Inhibitors - metabolism; Protease Inhibitors - pharmacology; Protein Conformation; Stromelysin; Structure-Activity Relationship; X‐ray structure; Zinc - metabolism
• ISSN: 0961-8368; 1469-896X
• DOI: 10.1110/ps.48401

A new class of matrix metalloproteinase (MMP) inhibitors has been identified by screening a collection of compounds against stromelysin. The inhibitors, 2,4,6‐pyrimidine triones, have proven to be potent inhibitors of gelatinases A and B. An X‐ray crystal structure of one representative compound bound to the catalytic domain of stromelysin shows that the compounds bind at the active site and ligand the active‐site zinc. The pyrimidine triones mimic 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 synthesized and assayed against stromelysin, and the variations in potency are explained in terms of the binding mode revealed in the X‐ray crystal structure.