The crystal structure of the complex of non-peptidic inhibitor of human neutrophil elastase ONO-6818 and porcine pancreatic elastase

Bioorg Med Chem. 2001 Mar;9(3):647-51. doi: 10.1016/s0968-0896(00)00277-7.

Abstract

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.

MeSH terms

  • Animals
  • Catalytic Domain
  • Crystallography, X-Ray
  • Humans
  • Leukocyte Elastase / antagonists & inhibitors*
  • Leukocyte Elastase / chemistry
  • Molecular Structure
  • Pancreatic Elastase / antagonists & inhibitors*
  • Pancreatic Elastase / chemistry
  • Protein Binding
  • Serine Proteinase Inhibitors / chemistry*
  • Serine Proteinase Inhibitors / metabolism
  • Swine

Substances

  • Serine Proteinase Inhibitors
  • Pancreatic Elastase
  • Leukocyte Elastase