4KWF

Crystal Structure Analysis of ALDH2+ALDiB33

4KWF の概要

• エントリーDOI: 10.2210/pdb4kwf/pdb
• 関連するPDBエントリー: 4KWG 4L1O
• 分子名称: Aldehyde dehydrogenase, mitochondrial, 1-benzyl-1H-indole-2,3-dione, SODIUM ION, ... (6 entities in total)
• 機能のキーワード: aldh2+aldib33, ketone binding, oxidoreductase-inhibitor complex, oxidoreductase/inhibitor
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Mitochondrion matrix: P05091
• タンパク質・核酸の鎖数: 8
• 化学式量合計: 433803.69

構造登録者

Hurley, T.D.,Kimble-Hill, A.C. (登録日: 2013-05-24, 公開日: 2014-04-09, 最終更新日: 2024-11-06)

主引用文献

Kimble-Hill, A.C.,Parajuli, B.,Chen, C.H.,Mochly-Rosen, D.,Hurley, T.D.
Development of selective inhibitors for aldehyde dehydrogenases based on substituted indole-2,3-diones.
J.Med.Chem., 57:714-722, 2014

PubMed Abstract: Aldehyde dehydrogenases (ALDH) participate in multiple metabolic pathways and have been indicated to play a role in several cancerous disease states. Our laboratory is interested in developing novel and selective ALDH inhibitors. We looked to further work recently published by developing a class of isoenzyme-selective inhibitors using similar indole-2,3-diones that exhibit differential inhibition of ALDH1A1, ALDH2, and ALDH3A1. Kinetic and X-ray crystallography data suggest that these inhibitors are competitive against aldehyde binding, forming direct interactions with active-site cysteine residues. The selectivity is precise in that these compounds appear to interact directly with the catalytic nucleophile, Cys243, in ALDH3A1 but not in ALDH2. In ALDH2, the 3-keto group is surrounded by the adjacent Cys301/303. Surprisingly, the orientation of the interaction changes depending on the nature of the substitutions on the basic indole ring structure and correlates well with the observed structure-activity relationships for each ALDH isoenzyme.

PubMed: 24444054
DOI: 10.1021/jm401377v

実験手法

X-RAY DIFFRACTION (2.31 Å)