6GXY

Tryparedoxin from Trypanosoma brucei in complex with CFT

6GXY の概要

• エントリーDOI: 10.2210/pdb6gxy/pdb
• 関連するPDBエントリー: 6GXG
• 分子名称: Tryparedoxin, 5-(4-fluorophenyl)-2-methyl-3~{H}-thieno[2,3-d]pyrimidin-4-one (3 entities in total)
• 機能のキーワード: covalent inhibitor, photoreduction, inhibitor-induced dimerization, monomer-dimer mixture, oxidoreductase
• 由来する生物種: Trypanosoma brucei brucei
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 48837.99

構造登録者

Bader, N.,Wagner, A.,Hellmich, U.,Schindelin, H. (登録日: 2018-06-27, 公開日: 2019-01-16, 最終更新日: 2024-01-17)

主引用文献

Wagner, A.,Le, T.A.,Brennich, M.,Klein, P.,Bader, N.,Diehl, E.,Paszek, D.,Weickhmann, A.K.,Dirdjaja, N.,Krauth-Siegel, R.L.,Engels, B.,Opatz, T.,Schindelin, H.,Hellmich, U.A.
Inhibitor-Induced Dimerization of an Essential Oxidoreductase from African Trypanosomes.
Angew. Chem. Int. Ed. Engl., 58:3640-3644, 2019

PubMed Abstract: Trypanosomal and leishmanial infections claim tens of thousands of lives each year. The metabolism of these unicellular eukaryotic parasites differs from the human host and their enzymes thus constitute promising drug targets. Tryparedoxin (Tpx) from Trypanosoma brucei is the essential oxidoreductase in the parasite's hydroperoxide-clearance cascade. In vitro and in vivo functional assays show that a small, selective inhibitor efficiently inhibits Tpx. With X-ray crystallography, SAXS, analytical SEC, SEC-MALS, MD simulations, ITC, and NMR spectroscopy, we show how covalent binding of this monofunctional inhibitor leads to Tpx dimerization. Intra- and intermolecular inhibitor-inhibitor, protein-protein, and inhibitor-protein interactions stabilize the dimer. The behavior of this efficient antitrypanosomal molecule thus constitutes an exquisite example of chemically induced dimerization with a small, monovalent ligand that can be exploited for future drug design.

PubMed: 30605929
DOI: 10.1002/anie.201810470

実験手法

X-RAY DIFFRACTION (1.8 Å)