RNA aptamer to thrombin binds anion-binding exosite-2 and alters protease inhibition by heparin-binding serpins

Martha L. Jeter, Linda V. Ly, Yolanda M. Fortenberry, Herbert C. Whinna, Rebekah R. White, Christopher P. Rusconi, Bruce A. Sullenger, Frank C. Church

Research output: Contribution to journalArticlepeer-review

Abstract

We studied the RNA aptamer Toggle-25/thrombin interaction during inhibition by antithrombin (AT), heparin cofactor II (HCII) and protein C inhibitor (PCI). Thrombin inhibition was reduced 3-fold by Toggle-25 for AT and HCII, but it was slightly enhanced for PCI. In the presence of glycosaminoglycans, AT and PCI had significantly reduced thrombin inhibition with Toggle-25, but it was only reduced 3-fold for HCII. This suggested that the primary effect of aptamer binding was through the heparin-binding site of thrombin, anion-binding exosite-2 (exosite-2). We localized the Toggle-25 binding site to Arg 98, Glu 169, Lys 174, Asp 175, Arg 245, and Lys 248 of exosite-2. We conclude that a RNA aptamer to thrombin exosite-2 might provide an effective clinical reagent to control heparin's anticoagulant action.

Original languageEnglish (US)
Pages (from-to)10-14
Number of pages5
JournalFEBS Letters
Volume568
Issue number1-3
DOIs
StatePublished - Jun 18 2004
Externally publishedYes

Keywords

  • AT, antithrombin
  • HCII, heparin cofactor II
  • Heparin
  • PCI, protein C inhibitor
  • RNA aptamer
  • Serpin
  • Serpin, serine protease inhibitor
  • Thrombin
  • exosite-1 and -2, anion-binding exosite-1 and anion-binding exosite-2

ASJC Scopus subject areas

  • Biophysics
  • Structural Biology
  • Biochemistry
  • Molecular Biology
  • Genetics
  • Cell Biology

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