Crystal structures of Staphylococcusaureus methionine aminopeptidase complexed with keto heterocycle and aminoketone inhibitors reveal the formation of a tetrahedral intermediate

High-resolution crystal structures of Staphylococcus aureus methionine aminopeptidase I in complex with various keto heterocycles and aminoketones were determined, and the intermolecular ligand interactions with the enzyme are reported. The compounds are effective inhibitors of the S. aureus enzyme...

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Published inJournal of medicinal chemistry Vol. 47; no. 6; pp. 1325 - 1328
Main Authors Douangamath, Alice, Dale, Glenn E, D'Arcy, Allan, Almstetter, Michael, Eckl, Robert, Frutos-Hoener, Annabelle, Henkel, Bernd, Illgen, Katrin, Nerdinger, Sven, Schulz, Henk, Mac Sweeney, Aengus, MacSweeney, Aengus, Thormann, Michael, Treml, Andreas, Pierau, Sabine, Wadman, Sjoerd, Oefner, Christian
Format Journal Article
LanguageEnglish
Published United States 11.03.2004
Subjects
Amines - chemistry
Aminopeptidases - antagonists & inhibitors
Aminopeptidases - chemistry
Binding Sites
Crystallography, X-Ray
Cyclopropanes - chemistry
Ketones - chemistry
Methionyl Aminopeptidases
Models, Molecular
Molecular Structure
Pyridines - chemistry
Staphylococcus aureus - enzymology
Thiazoles - chemistry
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Summary:High-resolution crystal structures of Staphylococcus aureus methionine aminopeptidase I in complex with various keto heterocycles and aminoketones were determined, and the intermolecular ligand interactions with the enzyme are reported. The compounds are effective inhibitors of the S. aureus enzyme because of the formation of an uncleavable tetrahedral intermediate upon binding. The electron densities unequivocally show the enzyme-catalyzed transition-state analogue mimicking that for amide bond hydrolysis of substrates.
Bibliography:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
ISSN:0022-2623
1520-4804