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Related Experiment Videos

Conformational changes in thrombin when complexed by serpins.

J C Fredenburgh1, A R Stafford, J I Weitz

  • 1Hamilton Civic Hospitals Research Centre and Department of Medicine, McMaster University, Hamilton, Ontario L8V 1C3, Canada.

The Journal of Biological Chemistry
|October 5, 2001
PubMed
Summary
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Serine protease inhibitors (serpins) disrupt thrombin

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Enzymology

Background:

  • Thrombin, a key enzyme in blood coagulation, features two exosites crucial for substrate and inhibitor binding.
  • These exosites also allosterically regulate thrombin's enzymatic activity.
  • Serpins are a diverse group of proteins that inhibit serine proteases, including thrombin.

Purpose of the Study:

  • To investigate how complex formation with different serpins (antithrombin, heparin cofactor II, and alpha(1)-antitrypsin) affects the structure and function of thrombin's exosites.
  • To determine the binding interactions and allosteric modulation of thrombin by these serpins.

Main Methods:

  • Utilized a hirudin-derived peptide to probe exosite 1 integrity and binding affinity.
  • Employed an exosite 1-binding DNA aptamer (HD-1) to assess serpin displacement.

Related Experiment Videos

  • Assessed thrombin's binding to fibrin in the presence of serpins.
  • Conducted protease sensitivity studies and analyzed crystallographic data of homologous complexes.

    • Main Results:

    • Complexation with heparin cofactor II or alpha(1)-antitrypsin abolished exosite 1 binding of the hirudin peptide.
    • The thrombin-antithrombin complex showed a 55-fold reduced affinity for the peptide.
    • All three serpins displaced bound peptide or aptamer from exosite 1.
    • Thrombin's binding to fibrin was abrogated upon complexation with serpins.
    • Exosite 1 function was lost upon serpin complexation, while exosite 2 integrity was largely retained with only modest alterations in binding to heparin or an exosite 2 aptamer.

    Conclusions:

    • Serpin binding leads to the loss of exosite 1 function in thrombin, irrespective of the serpin's interaction mode.
    • Exosite 2 function remains largely intact during serpin complexation.
    • Structural disorganization of exosite 1 upon serpin binding is supported by experimental and crystallographic evidence.