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PDBsum entry 1ny2
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Hydrolase/hydrolase inhibitor
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PDB id
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1ny2
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Contents |
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* Residue conservation analysis
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References listed in PDB file
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Key reference
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Title
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Mechanisms of arg-Pro-Pro-Gly-Phe inhibition of thrombin.
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Authors
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A.A.Hasan,
M.Warnock,
M.Nieman,
S.Srikanth,
F.Mahdi,
R.Krishnan,
A.Tulinsky,
A.H.Schmaier.
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Ref.
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Am J Physiol Heart Circ Physiol, 2003,
285,
H183.
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PubMed id
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Abstract
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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 biotinylated NATLDPRSFLLR of the thrombin cleavage
site on protease-activated receptor (PAR)1 from binding to the peptide RPPGC
(IC50 = 20 microM). The soluble recombinant extracellular domain of PAR1
(rPAR1EC) blocks biotinylated RPPGF binding to rPAR1EC (IC50 = 50 microM) 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 Arg41
and interacts with the active site of alpha-thrombin.
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