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6TKI

Tsetse thrombin inhibitor in complex with human alpha-thrombin - tetragonal form at 12.7keV

Summary for 6TKI
Entry DOI10.2210/pdb6tki/pdb
Related6TKG 6TKH
DescriptorThrombin light chain, Thrombin heavy chain, Tsetse thrombin inhibitor, ... (6 entities in total)
Functional Keywordsanticoagulant tyrosine sulfation posttranslational modification complex, blood clotting
Biological sourceHomo sapiens (Human)
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Total number of polymer chains3
Total formula weight40083.70
Authors
Calisto, B.M.,Ripoll-Rozada, J.,de Sanctis, D.,Pereira, P.J.B. (deposition date: 2019-11-28, release date: 2020-11-04, Last modification date: 2024-11-13)
Primary citationCalisto, B.M.,Ripoll-Rozada, J.,Dowman, L.J.,Franck, C.,Agten, S.M.,Parker, B.L.,Veloso, R.C.,Vale, N.,Gomes, P.,de Sanctis, D.,Payne, R.J.,Pereira, P.J.B.
Sulfotyrosine-Mediated Recognition of Human Thrombin by a Tsetse Fly Anticoagulant Mimics Physiological Substrates.
Cell Chem Biol, 28:26-, 2021
Cited by
PubMed Abstract: 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.
PubMed: 33096052
DOI: 10.1016/j.chembiol.2020.10.002
PDB entries with the same primary citation
Experimental method
X-RAY DIFFRACTION (1.8 Å)
Structure validation

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