6TKH

Tsetse thrombin inhibitor in complex with human alpha-thrombin - orthorhombic form at 7keV

6TKH の概要

• エントリーDOI: 10.2210/pdb6tkh/pdb
• 関連するPDBエントリー: 6TKG
• 分子名称: Thrombin light chain, Thrombin heavy chain, Tsetse thrombin inhibitor, ... (7 entities in total)
• 機能のキーワード: anticoagulant tyrosine sulfation posttranslational modification complex, blood clotting
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 40267.89

構造登録者

Calisto, B.M.,Ripoll-Rozada, J.,de Sanctis, D.,Pereira, P.J.B. (登録日: 2019-11-28, 公開日: 2020-11-04, 最終更新日: 2024-10-09)

主引用文献

Calisto, 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

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

実験手法

X-RAY DIFFRACTION (1.9 Å)