2WPF

Trypanosoma brucei trypanothione reductase in complex with 3,4- dihydroquinazoline inhibitor (DDD00085762)

2WPF の概要

• エントリーDOI: 10.2210/pdb2wpf/pdb
• 関連するPDBエントリー: 2WOI 2WOV 2WOW 2WP5 2WP6 2WPC 2WPE
• 分子名称: TRYPANOTHIONE REDUCTASE, FLAVIN-ADENINE DINUCLEOTIDE, 3-[(4S)-6-CHLORO-2-METHYL-4-(4-METHYLPHENYL)QUINAZOLIN-3(4H)-YL]-N,N-DIMETHYLPROPAN-1-AMINE, ... (6 entities in total)
• 機能のキーワード: oxidoreductase, trypanosomiasis, sleeping sickness, flavoprotein, redox-active center
• 由来する生物種: TRYPANOSOMA BRUCEI
• 細胞内の位置: Cytoplasm: P39051
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 219045.58

構造登録者

Alphey, M.S.,Patterson, S.,Fairlamb, A.H. (登録日: 2009-08-06, 公開日: 2010-10-13, 最終更新日: 2024-11-13)

主引用文献

Patterson, S.,Alphey, M.S.,Jones, D.C.,Shanks, E.J.,Street, I.P.,Frearson, J.A.,Wyatt, P.G.,Gilbert, I.H.,Fairlamb, A.H.
Dihydroquinazolines as a Novel Class of Trypanosoma Brucei Trypanothione Reductase Inhibitors: Discovery, Synthesis, and Characterization of Their Binding Mode by Protein Crystallography.
J.Med.Chem., 54:6514-, 2011

PubMed Abstract: Trypanothione reductase (TryR) is a genetically validated drug target in the parasite Trypanosoma brucei , the causative agent of human African trypanosomiasis. Here we report the discovery, synthesis, and development of a novel series of TryR inhibitors based on a 3,4-dihydroquinazoline scaffold. In addition, a high resolution crystal structure of TryR, alone and in complex with substrates and inhibitors from this series, is presented. This represents the first report of a high resolution complex between a noncovalent ligand and this enzyme. Structural studies revealed that upon ligand binding the enzyme undergoes a conformational change to create a new subpocket which is occupied by an aryl group on the ligand. Therefore, the inhibitor, in effect, creates its own small binding pocket within the otherwise large, solvent exposed active site. The TryR-ligand structure was subsequently used to guide the synthesis of inhibitors, including analogues that challenged the induced subpocket. This resulted in the development of inhibitors with improved potency against both TryR and T. brucei parasites in a whole cell assay.

PubMed: 21851087
DOI: 10.1021/JM200312V

実験手法

X-RAY DIFFRACTION (1.9 Å)