Mapping of the catalytic site of CHO-t-PA and the t-PA variant BM 06.022 by synthetic inhibitors and substrates

Protein Sci. 1992 Aug;1(8):1007-13. doi: 10.1002/pro.5560010806.

Abstract

BM 06.022 is a t-PA deletion variant that is produced as inactive inclusion bodies in Escherichia coli and transformed into the native form by an in vitro refolding process. Until now, no X-ray and NMR structures of BM 06.022 were available. Therefore a detailed kinetic analysis of the hydrolysis of peptide substrates and of the inhibition by several benzamidine-derived inhibitors was carried out in order to assess that the active site region of the protease domain of BM 06.022 is correctly structured in comparison with t-PA. Our data reveal that the single-chain as well as the two-chain form of BM 06.022 and native t-PA are similar in catalytic and in inhibitor binding properties. This indicates that the active site and the highly complex rearrangement of t-PA upon cleavage of the Arg275-Ile276 bond are maintained in BM 06.022.

Publication types

  • Comparative Study

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Benzamidines / pharmacology
  • Binding Sites
  • CHO Cells
  • Cricetinae
  • Escherichia coli / genetics
  • Humans
  • Kinetics
  • Molecular Sequence Data
  • Mutagenesis, Site-Directed
  • Oligopeptides / metabolism
  • Recombinant Proteins / antagonists & inhibitors
  • Recombinant Proteins / metabolism
  • Substrate Specificity
  • Thrombin / pharmacology
  • Tissue Plasminogen Activator / antagonists & inhibitors
  • Tissue Plasminogen Activator / genetics
  • Tissue Plasminogen Activator / metabolism*
  • Transfection
  • Trypsin / pharmacology

Substances

  • Benzamidines
  • Oligopeptides
  • Recombinant Proteins
  • Trypsin
  • Thrombin
  • Tissue Plasminogen Activator