X-ray diffraction analysis of the inhibition of porcine pancreatic elastase by a peptidyl trifluoromethylketone.
X-ray crystallographic data to 2.57 A resolution (1 A = 0.1 nm) have been measured for the complex of a peptidyl trifluoromethylketone inhibitor with porcine pancreatic elastase (PPE); R = 0.14. The inhibitor forms a stable complex with the enzyme by means of a covalent attachment to active site Ser195O gamma, resulting in a hemiketal moiety with tetrahedral geometry. The tripeptide protion binds as an antiparallel beta-sheet, with four hydrogen bonds augmenting the active-site covalent linkage, Ki = 9.5 microM. His57 exhibits a bifurcated H-bond to both Ser195O gamma and an F atom of the inhibitor. This study is one of a series which explores the binding geometry of a variety of small substrates and inhibitors to PPE. This peptidyl-PPE complex affords insight into the binding geometry of a novel trifluoromethylketone moiety to a serine proteinase.
Department of Chemistry, Texas A&M University, College Station 77843.
L H
LH
Takahashi
R
R
Radhakrishnan
R E
RE
Rosenfield
E F
EF
Meyer
D A
DA
Trainor
M
M
Stein
D000818:Animals; D001665:Binding Sites; D006860:Hydrogen Bonding; D009842:Oligopeptides / Q000494:pharmacology*; D010196:Pancreatic Elastase / Q000037:antagonists & inhibitors*; D013552:Swine; D014961:X-Ray Diffraction
D009842:Oligopeptides; C057216:acetylalanyl-prolyl-valyl-trifluoromethyl ketone; D010196:Pancreatic Elastase