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Thrombomodulin increases the rate of thrombin inhibition by BPTI.

Publication ,  Journal Article
Rezaie, AR; He, X; Esmon, CT
Published in: Biochemistry
January 13, 1998

Thrombin undergoes allosteric modulation by thrombomodulin (TM) that results in a shift in macromolecular specificity, blocking fibrinogen clotting while enhancing protein C activation. The TM enhancement of protein C activation involves both an 8-fold decrease in Km and a 200-fold increase in kcat. Although TM-mediated conformational changes in thrombin have been detected by many techniques, the nature of these changes remains obscure. Access to the active center of thrombin is relatively restricted due to the presence of a large insertion loop at residue 60 (chymotrypsin numbering) that has been implicated in modeling studies as being responsible for poor inhibition by BPTI. Thrombin and the E192Q mutant, which binds BPTI much more tightly than thrombin, are both inhibited very slowly by BPTI. TM increases the rate of thrombin or thrombin E192Q inhibition by BPTI approximately 10-fold. When analyzed as slow tight binding inhibition, the TM effect on thrombin E192Q inhibition by BPTI is primarily on the first, reversible step in the reaction. Structural studies of the thrombin E192Q-BPTI complex have previously shown that the 60 loop lies over the BPTI, a position which requires 8 A movement at the apex of the 60 loop, and that BPTI is found in the same canonical orientation as in the trypsin complex. It follows that TM enhancement of the initial interaction of thrombin results in a conformation that favors interactions with BPTI, probably involving motion of the 60 loop.

Duke Scholars

Published In

Biochemistry

DOI

ISSN

0006-2960

Publication Date

January 13, 1998

Volume

37

Issue

2

Start / End Page

693 / 699

Location

United States

Related Subject Headings

  • Trypsin Inhibitors
  • Thrombomodulin
  • Thrombin
  • Protein Conformation
  • Protein Binding
  • Mutation
  • Glutamic Acid
  • Drug Interactions
  • Biochemistry & Molecular Biology
  • Binding Sites
 

Citation

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Rezaie, A. R., He, X., & Esmon, C. T. (1998). Thrombomodulin increases the rate of thrombin inhibition by BPTI. Biochemistry, 37(2), 693–699. https://doi.org/10.1021/bi971271y
Rezaie, A. R., X. He, and C. T. Esmon. “Thrombomodulin increases the rate of thrombin inhibition by BPTI.Biochemistry 37, no. 2 (January 13, 1998): 693–99. https://doi.org/10.1021/bi971271y.
Rezaie AR, He X, Esmon CT. Thrombomodulin increases the rate of thrombin inhibition by BPTI. Biochemistry. 1998 Jan 13;37(2):693–9.
Rezaie, A. R., et al. “Thrombomodulin increases the rate of thrombin inhibition by BPTI.Biochemistry, vol. 37, no. 2, Jan. 1998, pp. 693–99. Pubmed, doi:10.1021/bi971271y.
Rezaie AR, He X, Esmon CT. Thrombomodulin increases the rate of thrombin inhibition by BPTI. Biochemistry. 1998 Jan 13;37(2):693–699.
Journal cover image

Published In

Biochemistry

DOI

ISSN

0006-2960

Publication Date

January 13, 1998

Volume

37

Issue

2

Start / End Page

693 / 699

Location

United States

Related Subject Headings

  • Trypsin Inhibitors
  • Thrombomodulin
  • Thrombin
  • Protein Conformation
  • Protein Binding
  • Mutation
  • Glutamic Acid
  • Drug Interactions
  • Biochemistry & Molecular Biology
  • Binding Sites