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.
Douangamath
Alice
A
Morphochem AG, WRO-1055/388, Schwarzwaldallee 215, CH-4058 Basel, Switzerland.
Dale
Glenn E
GE
D'Arcy
Allan
A
Almstetter
Michael
M
Eckl
Robert
R
Frutos-Hoener
Annabelle
A
Henkel
Bernd
B
Illgen
Katrin
K
Nerdinger
Sven
S
Schulz
Henk
H
Mac Sweeney
Aengus
A
MacSweeney
Aengus
A
Thormann
Michael
M
Treml
Andreas
A
Pierau
Sabine
S
Wadman
Sjoerd
S
Oefner
Christian
C
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