Structural characterizations of nonpeptidic thiadiazole inhibitors of matrix metalloproteinases reveal the basis for stromelysin selectivity
| Autor: | Heinrich J. Schostarez, R. A. Poorman, J. W. Wilks, Vincent P. Marshall, C. M. Trepod, G. L. Petzold, John E. Mott, G. F. Hess, G.L. Bryant Jr, T. J. O'Sullivan, Barry C. Finzel, M. A. Mitchell, Eric T. Baldwin |
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| Rok vydání: | 1998 |
| Předmět: |
Models
Molecular Matrix Metalloproteinase 3 Protein Conformation Stereochemistry Matrix Metalloproteinase Inhibitors Matrix metalloproteinase Crystallography X-Ray Biochemistry Protein structure Thiadiazoles Hydrolase Animals Urea Collagenases Enzyme Inhibitors Binding site Molecular Biology chemistry.chemical_classification Binding Sites Molecular Structure biology Active site Hydrogen Bonding Zinc Enzyme chemistry Vertebrates biology.protein Protein Binding Research Article |
| Zdroj: | Protein Science. 7:2118-2126 |
| ISSN: | 1469-896X 0961-8368 |
| DOI: | 10.1002/pro.5560071008 |
| Popis: | The binding of two 5-substituted-1,3,4-thiadiazole-2-thione inhibitors to the matrix metalloproteinase stromelysin (MMP-3) have been characterized by protein crystallography. Both inhibitors coordinate to the catalytic zinc cation via an exocyclic sulfur and lay in an unusual position across the unprimed (P1-P3) side of the proteinase active site. Nitrogen atoms in the thiadiazole moiety make specific hydrogen bond interactions with enzyme structural elements that are conserved across all enzymes in the matrix metalloproteinase class. Strong hydrophobic interactions between the inhibitors and the side chain of tyrosine-155 appear to be responsible for the very high selectivity of these inhibitors for stromelysin. In these enzyme/inhibitor complexes, the S1' enzyme subsite is unoccupied. A conformational rearrangement of the catalytic domain occurs that reveals an inherent flexibility of the substrate binding region leading to speculation about a possible mechanism for modulation of stromelysin activity and selectivity. |
| Databáze: | OpenAIRE |
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