Novel mechanism of inhibition of elastase by beta-lactams is defined by two inhibitor crystal complexes.
Two structurally related beta-lactams form different covalent complexes upon reaction with porcine elastase. The high resolution x-ray structures of these two complexes provide a clear insight into the mechanism of the reaction and suggest the design of a new class of serine protease inhibitors that resist enzyme reactivation by hydrolysis of the acyl intermediate. The presence of a hydroxyethyl substituent on the beta-lactam ring provides a new reaction pathway resulting in the elimination of the hydroxyethyl group and the formation of a stabilizing conjugated double bond system. In contrast, the presence of a diethyl substituent on the beta-lactam ring leads to addition of water. The two enzyme complexes show very different binding modes in the enzyme active site.
Taylor
P
P
Structural Biochemistry Group, The Edinburgh Centre for Protein Technology, Institute of Cell and Molecular Biology, The University of Edinburgh, Michael Swann Building, King's Buildings, Mayfield Road, Edinburgh EH9 3JR, United Kingdom.
Anderson
V
V
Dowden
J
J
Flitsch
S L
SL
Turner
N J
NJ
Loughran
K
K
Walkinshaw
M D
MD
D000818:Animals; D001665:Binding Sites; D003460:Crystallization; D018360:Crystallography, X-Ray; D006860:Hydrogen Bonding; D008958:Models, Molecular; D015394:Molecular Structure; D010196:Pancreatic Elastase / Q000037:antagonists & inhibitors / Q000737:chemistry*; D011485:Protein Binding; D015842:Serine Proteinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D013552:Swine; D047090:beta-Lactams / Q000494:pharmacology*
D015842:Serine Proteinase Inhibitors; D047090:beta-Lactams; D010196:Pancreatic Elastase