5ABM

Sheep aldehyde dehydrogenase 1A1

5ABM の概要

• エントリーDOI: 10.2210/pdb5abm/pdb
• 関連するPDBエントリー: 5AC0 5AC1 5AC2
• 分子名称: RETINAL DEHYDROGENASE 1, [[(2R,3S,4R,5R)-5-[(3R)-3-aminocarbonyl-3,4-dihydro-2H-pyridin-1-yl]-3,4-bis(oxidanyl)oxolan-2-yl]methoxy-oxidanidyl-ph osphoryl] [(2R,3S,4R,5R)-5-(6-aminopurin-9-yl)-3,4-bis(oxidanyl)oxolan-2-yl]methyl phosphate, MAGNESIUM ION, ... (4 entities in total)
• 機能のキーワード: oxidoreductase, oxidation-reduction process, activity
• 由来する生物種: OVIS ARIES (SHEEP)
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 221784.61

構造登録者

Koch, M.F.,Harteis, S.,Blank, I.D.,Pestel, G.,Tietze, L.F.,Ochsenfeld, C.,Schneider, S.,Sieber, S.A. (登録日: 2015-08-07, 公開日: 2015-09-16, 最終更新日: 2024-01-10)

主引用文献

Koch, M.F.,Harteis, S.,Blank, I.D.,Pestel, G.,Tietze, L.F.,Ochsenfeld, C.,Schneider, S.,Sieber, S.A.
Structural, Biochemical, and Computational Studies Reveal the Mechanism of Selective Aldehyde Dehydrogenase 1A1 Inhibition by Cytotoxic Duocarmycin Analogues.
Angew.Chem.Int.Ed.Engl., 54:13550-, 2015

PubMed Abstract: Analogues of the natural product duocarmycin bearing an indole moiety were shown to bind aldehyde dehydrogenase 1A1 (ALDH1A1) in addition to DNA, while derivatives without the indole solely addressed the ALDH1A1 protein. The molecular mechanism of selective ALDH1A1 inhibition by duocarmycin analogues was unraveled through cocrystallization, mutational studies, and molecular dynamics simulations. The structure of the complex shows the compound embedded in a hydrophobic pocket, where it is stabilized by several crucial π-stacking and van der Waals interactions. This binding mode positions the cyclopropyl electrophile for nucleophilic attack by the noncatalytic residue Cys302, thereby resulting in covalent attachment, steric occlusion of the active site, and inhibition of catalysis. The selectivity of duocarmycin analogues for ALDH1A1 is unique, since only minor alterations in the sequence of closely related protein isoforms restrict compound accessibility.

PubMed: 26373694
DOI: 10.1002/ANIE.201505749

実験手法

X-RAY DIFFRACTION (1.7 Å)