The crystal structure of the complex of non-peptidic inhibitor of human neutrophil elastase ONO-6818 and porcine pancreatic elastase.
The crystal structure of a new inhibitor of human neutrophil elastase (HNE), N-[2-[5-(tert-butyl)-1,3,4-oxadiazol-2-yl]-(IRS)-1-(methylethyl)-2-oxoethyl]-2-(5-amino-6-oxo-2-phenyl-6H-pyrimidin-1-ly)acetamide (ONO-6818, 1) complexed to porcine pancreatic elastase (PPE) has been determined at 1.86 A resolution. Analytical results provided evidence of a 1:1 complex in which the electrophilic ketone of 1 covalently bound to O gamma of Ser195 at the active site of PPE. The role of the unique electron-withdrawing ketone of 1 has been elucidated.
Odagaki
Y
Y
Minase Research Institute, Ono Pharmaceutical Co., Ltd. Mishima-Gun, Osaka, Japan. odagaki@ono.co.jp
Ohmoto
K
K
Matsuoka
S
S
Hamanaka
N
N
Nakai
H
H
Toda
M
M
Katsuya
Y
Y
D000818:Animals; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D006801:Humans; D019272:Leukocyte Elastase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D015394:Molecular Structure; D010196:Pancreatic Elastase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D011485:Protein Binding; D015842:Serine Proteinase Inhibitors / Q000737:chemistry* / Q000378:metabolism; D013552:Swine
D015842:Serine Proteinase Inhibitors; D010196:Pancreatic Elastase; D019272:Leukocyte Elastase