Novel mechanism of inhibition of elastase by beta-lactams is defined by two inhibitor crystal complexes

P Taylor, V Anderson, J Dowden, S L Flitsch, N J Turner, K Loughran, M D Walkinshaw

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

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.
Original languageEnglish
Pages (from-to)24901-5
Number of pages5
JournalJournal of Biological Chemistry
Volume274
Issue number35
Publication statusPublished - 1999

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