Inhibition of interleukin-1 beta converting enzyme by the cowpox virus serpin CrmA. An example of cross-class inhibition

J Biol Chem. 1994 Jul 29;269(30):19331-7.


We reported previously that human interleukin-1 beta converting enzyme (ICE) is regulated by the CrmA serpin encoded by cowpox virus. We now report the mechanism and kinetics of this unusual inhibition of a cysteine proteinase by a member of the serpin superfamily previously thought to inhibit serine proteinase only. CrmA possesses several characteristics typical of a number of inhibitory serpins. It is conformationally unstable, unfolding around 3 M urea, and stable to denaturation in 8 M urea upon complex formation with ICE. CrmA rapidly inhibits ICE with an association rate constant (kon) of 1.7 x 10(7) M-1 s-1, forming a tight complex with an equilibrium constant for inhibition (Ki) of less than 4 x 10(-12) M. These data indicate that CrmA is a potent inhibitor of ICE, consistent with the dramatic effects of CrmA on modifying host responses to virus infection. The inhibition of ICE by CrmA is an example of a "cross-class" interaction, in which a serpin inhibits a non-serine proteinase. Since CrmA possesses characteristics shared by inhibitors of serine proteinases, we presume that ICE, though it is a cysteine proteinase, has a substrate binding geometry strikingly close to that of serine proteinases. We reason that it is the substrate binding geometry, not the catalytic mechanism of a proteinase, that dictates its reactivity with protein inhibitors.

Publication types

  • Comparative Study
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Caspase 1
  • Cowpox virus / enzymology*
  • Cysteine Endopeptidases / classification
  • Cysteine Endopeptidases / metabolism
  • Glutathione Transferase / genetics
  • Glutathione Transferase / metabolism
  • Kinetics
  • Metalloendopeptidases / metabolism*
  • Molecular Sequence Data
  • Recombinant Fusion Proteins / metabolism
  • Serine Endopeptidases / metabolism
  • Serpins / metabolism*
  • Viral Proteins*


  • Recombinant Fusion Proteins
  • Serpins
  • Viral Proteins
  • interleukin-1beta-converting enzyme inhibitor
  • Glutathione Transferase
  • Serine Endopeptidases
  • Cysteine Endopeptidases
  • Caspase 1
  • Metalloendopeptidases