Kinetic dissection of α1-antitrypsin inhibition mechanism

Jong Shik Shin, Myeong Hee Yu

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20 Citations (Scopus)


Serpins (serine protease inhibitors) inhibit target proteases by forming a stable covalent complex in which the cleaved reactive site loop of the serpin is inserted into β-sheet A of the serpin with concomitant translocation of the protease to the opposite of the initial binding site. Despite recent determination of the crystal structures of a Michaelis protease-serpin complex as well as a stable covalent complex, details on the kinetic mechanism remain unsolved mainly due to difficulties in measuring kinetic parameters of acylation, protease translocation, and deacylation steps. To address the problem, we applied a mathematical model developed on the basis of a suicide inhibition mechanism to the stopped-flow kinetics of fluorescence resonance energy transfer during complex formation between α1-antitrypsin, a prototype serpin, and proteases. Compared with the hydrolysis of a peptide substrate, acylation of the protease by α1-antitrypsin is facilitated, whereas deacylation of the acyl intermediate is strongly suppressed during the protease translocation. The results from nucleophile susceptibility of the acyl intermediate suggest strongly that the active site of the protease is already perturbed during translocation.

Original languageEnglish
Pages (from-to)11629-11635
Number of pages7
JournalJournal of Biological Chemistry
Issue number14
Publication statusPublished - 2002 Apr 5

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology


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