The role of the protein core in the inhibitory power of the classic serine protease inhibitor, chymotrypsin inhibitor 2

Evette S. Radisky, David S. King, Gene Kwan, Daniel E. Koshland

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Abstract

A synthetic cyclic peptide, reported to be a tight-binding inhibitor of serine proteases, is instead found to be a good substrate, as is the linear peptide of the same sequence. Both of the peptides, designed to mimic the binding loop of chymotrypsin inhibitor 2 (CI2), were cleaved by subtilisin primarily at the CI2 reactive site Met-59-Glu-60 bond, revealing that the sequence, in the absence of the structural context of the inhibitor, provides sufficient specificity for hydrolysis of this bond. Insights from the crystal structure of the CI2/subtilisin complex, together with biochemical analysis of a CI2 Gly-83 deletion mutant, have allowed us to identify key features that make CI2 an effective inhibitor, while the cyclic and linear peptides are substrates.

Original languageEnglish (US)
Pages (from-to)6484-6492
Number of pages9
JournalBiochemistry
Volume42
Issue number21
DOIs
StatePublished - Jun 3 2003

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ASJC Scopus subject areas

  • Biochemistry

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