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Am J Physiol Heart Circ Physiol (February 21, 2003). doi:10.1152/ajpheart.00490.2002
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Submitted on June 11, 2002
Accepted on February 3, 2003

THE MECHANISMS OF ARG-PRO-PRO-GLY-PHE INHIBITION OF THROMBIN

Ahmed A. Hasan1, Mark Warnock2, Marvin Nieman2, Sujata Srikanth3, Fakhri Mahdi3, Raman Krishnan4, Alexander Tulinsky4, and Alvin H. Schmaier1*

1 Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA; Thromgen, Inc., Ann Arbor, MI, USA
2 Thromgen, Inc., Ann Arbor, MI, USA
3 Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA
4 Department of Chemistry, Michigan State University, East Lansing, MI, USA

* To whom correspondence should be addressed. E-mail: aschmaie{at}umich.edu.

Investigations determined the mechanism(s) by which Arg-Pro-Pro-Gly-Phe (RPPGF) inhibits thrombin-induced platelet activation. High concentrations of RPPGF inhibit thrombin-induced coagulant activity. RPPGF binds to the active site of thrombin by forming a parallel {beta}-strand with Ser214-Gly216 and interacts with His57, Asp189, and Ser195 of the catalytic triad. RPPGF competitively inhibits {alpha}-thrombin from hydrolyzing Sar-Pro-Arg-paranitroanilide with a Ki = 1.75 ± 0.03 mM. Other mechanisms were sought to explain why RPPGF inhibits thrombin activation of platelets at concentrations below that which inhibits its active site. Soluble RPPGF blocks peptide biotin-NATLDPRSFLLR of the thrombin cleavage site on protease activated receptor 1 (PAR1) from binding to peptide RPPGC (IC50 = 20 µM). Soluble recombinant extracellular domain of protease activated receptor 1 (rPAR1EC) blocks biotin-RPPGF binding to rPAR1EC (IC50 = 50 µM) bound to microtiter plates, but rPAR1EC deletion mutants missing the sequence LDPR or PRSF do not. RPPGF and related forms prevent the thrombin-like enzyme, thrombocytin, from proteolyzing rPAR1EC at concentrations that do not block thrombocytin's active site. These studies indicate that RPPGF is a bifunctional inhibitor of thrombin: it binds to PAR1 to prevent thrombin cleavage at arginine41 and interacts with {alpha}-thrombin's active site.




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