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 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.
Morphochem AG, WRO-1055/388, Schwarzwaldallee 215, CH-4058 Basel, Switzerland.
Alice
A
Douangamath
Glenn E
GE
Dale
Allan
A
D'Arcy
Michael
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Almstetter
Robert
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Eckl
Annabelle
A
Frutos-Hoener
Bernd
B
Henkel
Katrin
K
Illgen
Sven
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Nerdinger
Henk
H
Schulz
Aengus
A
Mac Sweeney
Aengus
A
MacSweeney
Michael
M
Thormann
Andreas
A
Treml
Sabine
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Pierau
Sjoerd
S
Wadman
Christian
C
Oefner
D000588:Amines / Q000737:chemistry*; D000626:Aminopeptidases / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D001665:Binding Sites; D018360:Crystallography, X-Ray; D003521:Cyclopropanes / Q000737:chemistry; D007659:Ketones / Q000737:chemistry*; D063208:Methionyl Aminopeptidases; D008958:Models, Molecular; D015394:Molecular Structure; D011725:Pyridines / Q000737:chemistry*; D013211:Staphylococcus aureus / Q000201:enzymology*; D013844:Thiazoles / Q000737:chemistry*
D000588:Amines; D003521:Cyclopropanes; D007659:Ketones; D011725:Pyridines; D013844:Thiazoles; D000626:Aminopeptidases; D063208:Methionyl Aminopeptidases