4WP7

Structure of human ALDH1A1 with inhibitor CM026

4WP7 の概要

• エントリーDOI: 10.2210/pdb4wp7/pdb
• 分子名称: Retinal dehydrogenase 1, YTTERBIUM (III) ION, 8-{[4-(furan-2-ylcarbonyl)piperazin-1-yl]methyl}-1,3-dimethyl-7-(3-methylbutyl)-3,7-dihydro-1H-purine-2,6-dione, ... (5 entities in total)
• 機能のキーワード: oxidoreductase enzyme inhibitor, oxidoreductase-oxidoreductase inhibitor complex, oxidoreductase/oxidoreductase inhibitor
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 55721.63

構造登録者

Morgan, C.A.,Hurley, T.D. (登録日: 2014-10-17, 公開日: 2015-02-11, 最終更新日: 2023-12-27)

主引用文献

Morgan, C.A.,Hurley, T.D.
Characterization of Two Distinct Structural Classes of Selective Aldehyde Dehydrogenase 1A1 Inhibitors.
J.Med.Chem., 58:1964-1975, 2015

PubMed Abstract: Aldehyde dehydrogenases (ALDH) catalyze the irreversible oxidation of aldehydes to their corresponding carboxylic acid. Alterations in ALDH1A1 activity are associated with such diverse diseases as cancer, Parkinson's disease, obesity, and cataracts. Inhibitors of ALDH1A1 could aid in illuminating the role of this enzyme in disease processes. However, there are no commercially available selective inhibitors for ALDH1A1. Here we characterize two distinct chemical classes of inhibitors that are selective for human ALDH1A1 compared to eight other ALDH isoenzymes. The prototypical members of each structural class, CM026 and CM037, exhibit submicromolar inhibition constants but have different mechanisms of inhibition. The crystal structures of these compounds bound to ALDH1A1 demonstrate that they bind within the aldehyde binding pocket of ALDH1A1 and exploit the presence of a unique glycine residue to achieve their selectivity. These two novel and selective ALDH1A1 inhibitors may serve as chemical tools to better understand the contributions of ALDH1A1 to normal biology and to disease states.

PubMed: 25634381
DOI: 10.1021/jm501900s

実験手法

X-RAY DIFFRACTION (1.8 Å)