4JN1

An Antidote for Dabigatran

4JN1 の概要

• エントリーDOI: 10.2210/pdb4jn1/pdb
• 関連するPDBエントリー: 4JN2
• 分子名称: anti-dabigatran Fab1, heavy chain, anti-dabigatran Fab1, light chain, GLYCEROL, ... (4 entities in total)
• 機能のキーワード: igg fragment binding dabigatran, immune system
• 由来する生物種: Mus musculus (mouse); 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 48573.31

構造登録者

Schiele, F.,Nar, H. (登録日: 2013-03-14, 公開日: 2013-03-27, 最終更新日: 2024-10-16)

主引用文献

Schiele, F.,van Ryn, J.,Canada, K.,Newsome, C.,Sepulveda, E.,Park, J.,Nar, H.,Litzenburger, T.
A specific antidote for dabigatran: functional and structural characterization.
Blood, 121:3554-3562, 2013

PubMed Abstract: Dabigatran etexilate is a direct thrombin inhibitor and used widely as an anticoagulant for the prevention of stroke in patients with atrial fibrillation. However, anticoagulation therapy can be associated with an increased risk of bleeding. Here, we present data on the identification, humanization, and in vitro pharmacology of an antidote for dabigatran (aDabi-Fab). The X-ray crystal structure of dabigatran in complex with the antidote reveals many structural similarities of dabigatran recognition compared with thrombin. By a tighter network of interactions, the antidote achieves an affinity for dabigatran that is ~350 times stronger than its affinity for thrombin. Despite the structural similarities in the mode of dabigatran binding, the antidote does not bind known thrombin substrates and has no activity in coagulation tests or platelet aggregation. In addition we demonstrate that the antidote rapidly reversed the anticoagulant activity of dabigatran in vivo in a rat model of anticoagulation. This is the first report of a specific antidote for a next-generation anticoagulant that may become a valuable tool in patients who require emergency procedures.

PubMed: 23476049
DOI: 10.1182/blood-2012-11-468207

実験手法

X-RAY DIFFRACTION (1.89 Å)