A classical peptide inhibitor of serine proteases that is hydrolyzed ≈ 107 times more slowly than a good substrate is shown to form an acyl-enzyme intermediate rapidly. Despite this quick first step, further reaction is slowed dramatically because of tight and oriented binding of the cleaved peptide, preventing acyl-enzyme hydrolysis and favoring the reverse reaction. Moreover, this mechanism appears to be common to a large class of tight-binding serine protease inhibitors that mimic good substrates. The arrest of enzymatic reaction at the intermediate stage allowed us to determine that the consensus nucleophilic attack angle is close to 90° in the reactive Michaelis complexes.
|Original language||English (US)|
|Number of pages||6|
|Journal||Proceedings of the National Academy of Sciences of the United States of America|
|State||Published - Aug 2002|
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