Structural, Biochemical, and Computational Studies Reveal the Mechanism of Selective Aldehyde Dehydrogenase 1A1 Inhibition by Cytotoxic Duocarmycin Analogues

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 analogue...

Full description

Saved in:
Bibliographic Details
Published in:Angewandte Chemie 2015-11, Vol.127 (46), p.13754-13758
Main Authors: Koch, Maximilian F., Harteis, Sabrina, Blank, Iris D., Pestel, Galina, Tietze, Lutz F., Ochsenfeld, Christian, Schneider, Sabine, Sieber, Stephan A.
Format: Article
Language:eng ; ger
Subjects:
Aldehydes
ALDH1A1
Chemistry
Computer simulation
Derivatives
Duocarmycin
Enzyme
Indoles
Inhibition
Inhibitoren
Molecular dynamics
Molecular structure
Proteins
Proteinstrukturen
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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. Passgenau: Duocarmycin‐Analoga zeigen eine einzigartige Selektivität für ALDH1A1. Der molekulare Ursprung dieser Präferenz wurde durch Kokristallisation, Moleküldynamikrechnungen, Mutationsstudien und kinetische Analysen aufgeklärt. Das Molekül passt genau in eine maßgeschneiderte Bindetasche der ALDH1A1, jedoch nicht in die verwandter Isoformen und wird innerhalb der Bindetasche durch π‐π‐ und Van‐der‐Waals‐Wechselwirkungen stabilisiert.
ISSN:0044-8249
1521-3757
DOI:10.1002/ange.201505749