5AC2

human aldehyde dehydrogenase 1A1 with duocarmycin analog

Summary for 5AC2

• Entry DOI: 10.2210/pdb5ac2/pdb
• Related: 5ABM 5AC0 5AC1
• Descriptor: RETINAL DEHYDROGENASE 1, 1-[(1S)-1-methyl-5-oxidanyl-1,2-dihydrobenzo[e]indol-3-yl]hexan-1-one, YTTERBIUM (III) ION, ... (5 entities in total)
• Functional Keywords: oxidoreductase, oxidation-reduction process, aldehyde dehydrogenase activity
• Biological source: HOMO SAPIENS (HUMAN)
• Cellular location: Cytoplasm: P00352
• Total number of polymer chains: 1
• Total formula weight: 56408.59

Authors

Koch, M.F.,Harteis, S.,Blank, I.D.,Pestel, G.,Tietze, L.F.,Ochsenfeld, C.,Schneider, S.,Sieber, S.A. (deposition date: 2015-08-11, release date: 2015-08-26, Last modification date: 2024-11-06)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (1.85 Å)