6BU7

Crystal structure of Trypanothione Reductase from Trypanosoma brucei in complex with inhibitor RD130 1-[2-(Piperidin-4-yl)ethyl]-5-{5-[1-(pyrrolidin-1-yl)cyclohexyl]-1,3-thiazol-2-yl}-1H-indole

6BU7 の概要

• エントリーDOI: 10.2210/pdb6bu7/pdb
• 関連するPDBエントリー: 4NEV 6BTL
• 分子名称: Trypanothione reductase, FLAVIN-ADENINE DINUCLEOTIDE, SULFATE ION, ... (7 entities in total)
• 機能のキーワード: trypanosoma, inhibitor, complex, sleeping sickness, oxidoreductase-inhibitor complex, oxidoreductase/inhibitor
• 由来する生物種: Trypanosoma brucei brucei (strain 927/4 GUTat10.1)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 110817.73

構造登録者

Bryson, S.,De Gasparo, R.,Krauth-Siegel, R.L.,Diederich, F.,Pai, E.F. (登録日: 2017-12-08, 公開日: 2018-06-06, 最終更新日: 2024-11-06)

主引用文献

De Gasparo, R.,Brodbeck-Persch, E.,Bryson, S.,Hentzen, N.B.,Kaiser, M.,Pai, E.F.,Krauth-Siegel, R.L.,Diederich, F.
Biological Evaluation and X-ray Co-crystal Structures of Cyclohexylpyrrolidine Ligands for Trypanothione Reductase, an Enzyme from the Redox Metabolism of Trypanosoma.
ChemMedChem, 13:957-967, 2018

PubMed Abstract: The tropical diseases human African trypanosomiasis, Chagas disease, and the various forms of leishmaniasis are caused by parasites of the family of trypanosomatids. These protozoa possess a unique redox metabolism based on trypanothione and trypanothione reductase (TR), making TR a promising drug target. We report the optimization of properties and potency of cyclohexylpyrrolidine inhibitors of TR by structure-based design. The best inhibitors were freely soluble and showed competitive inhibition constants (K ) against Trypanosoma (T.) brucei TR and T. cruzi TR and in vitro activities (half-maximal inhibitory concentration, IC ) against these parasites in the low micromolar range, with high selectivity against human glutathione reductase. X-ray co-crystal structures confirmed the binding of the ligands to the hydrophobic wall of the "mepacrine binding site" with the new, solubility-providing vectors oriented toward the surface of the large active site.

PubMed: 29624890
DOI: 10.1002/cmdc.201800067

実験手法

X-RAY DIFFRACTION (2.73 Å)