An X-ray Crystallographic Analysis of UDP-N-acetylglucosamine 1-Carboxyvinyl Transferase Complexed with UDP-N-acetylglucosamine Fromhaemophilus Influenzae

Human neutrophil elastase (HNE) has been shown to contribute to the pathogenesis of destructive disease, such as acute respiratory distress syndrome, ischemia-reperfusion injury and multiple organ failure.Watersoluble HNE inhibitor that can be easily administrated intravenously would be desired for the treatment of such acute disorders.AE-3763 has potent in vivo activity (ED50=0.42mg/kg/hr on lung hemorrhage induced by HNE in hamsters) and high solubility (1g/ml H2O).We have determined the crystal structure of porcine pancreatic elastase complexed with AE-3763 at 1.55 Å resolution.A final complex model had crystallographic R-factor less than 0.19.A clear electron density was observed for the inhibitor molecule in the active site.In this presentation, we will describe the X-ray crystallographic study of the interaction of AE-3763 with the active site of PPE.AE-3763:S-[2-(3carboxymethyl-2-oxo-1-imidazolidinyl)-acetyl]-L-valyl-N-(3,3,3,-trifluoro-1isopropyl)-2-oxopropyl-L-prolinamide