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PDBsum entry 6tkh
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Blood clotting
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PDB id
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6tkh
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References listed in PDB file
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Key reference
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Title
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Sulfotyrosine-Mediated recognition of human thrombin by a tsetse fly anticoagulant mimics physiological substrates.
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Authors
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B.M.Calisto,
J.Ripoll-Rozada,
L.J.Dowman,
C.Franck,
S.M.Agten,
B.L.Parker,
R.C.Veloso,
N.Vale,
P.Gomes,
D.De sanctis,
R.J.Payne,
P.J.B.Pereira.
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Ref.
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Cell Chem Biol, 2021,
28,
26.
[DOI no: ]
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PubMed id
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Abstract
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Despite possessing only 32 residues, the tsetse thrombin inhibitor (TTI) is
among the most potent anticoagulants described, with sub-picomolar inhibitory
activity against thrombin. Unexpectedly, TTI isolated from the fly is 2000-fold
more active and 180 Da heavier than synthetic and recombinant variants. We
predicted the presence of a tyrosine O-sulfate post-translational modification
of TTI, prompting us to investigate the effect of the modification on
anticoagulant activity. A combination of chemical synthesis and functional
assays was used to reveal that sulfation significantly improved the inhibitory
activity of TTI against thrombin. Using X-ray crystallography, we show that the
N-terminal sulfated segment of TTI binds the basic exosite II of thrombin,
establishing interactions similar to those of physiologic substrates, while the
C-terminal segment abolishes the catalytic activity of thrombin. This
non-canonical mode of inhibition, coupled with its potency and small size, makes
TTI an attractive scaffold for the design of novel antithrombotics.
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