title: Structural, Biochemical, and Computational Studies Reveal the Mechanism of Selective Aldehyde Dehydrogenase 1A1 Inhibition by Cytotoxic Duocarmycin Analogues.
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.
authors.affiliation: Center for Integrated Protein Science Munich CIPSMDepartment of Chemistry, Technische Universität München, Lichtenbergstrasse 4, 85747 Garching (Germany).
authors.forename: Maximilian F
authors.initials: MF
authors.lastname: Koch
authors.affiliation: Center for Integrated Protein Science Munich CIPSMDepartment of Chemistry, Technische Universität München, Lichtenbergstrasse 4, 85747 Garching (Germany).
authors.forename: Sabrina
authors.initials: S
authors.lastname: Harteis
authors.affiliation: Center for Integrated Protein Science Munich CIPSMDepartment of Chemistry, University of Munich, Butenandtstrasse 7 (C), 81377 München (Germany).
authors.forename: Iris D
authors.initials: ID
authors.lastname: Blank
authors.affiliation: Institute of Organic and Biomolecular Chemistry, Georg-August-Universität Göttingen, Tammannstrasse 2, 37033 Göttingen (Germany).
authors.forename: Galina
authors.initials: G
authors.lastname: Pestel
authors.affiliation: Institute of Organic and Biomolecular Chemistry, Georg-August-Universität Göttingen, Tammannstrasse 2, 37033 Göttingen (Germany).
authors.forename: Lutz F
authors.initials: LF
authors.lastname: Tietze
authors.affiliation: Center for Integrated Protein Science Munich CIPSMDepartment of Chemistry, University of Munich, Butenandtstrasse 7 (C), 81377 München (Germany).
authors.forename: Christian
authors.initials: C
authors.lastname: Ochsenfeld
authors.affiliation: Center for Integrated Protein Science Munich CIPSMDepartment of Chemistry, Technische Universität München, Lichtenbergstrasse 4, 85747 Garching (Germany). sabine.schneider@mytum.de.
authors.forename: Sabine
authors.initials: S
authors.lastname: Schneider
authors.affiliation: Center for Integrated Protein Science Munich CIPSMDepartment of Chemistry, Technische Universität München, Lichtenbergstrasse 4, 85747 Garching (Germany). stephan.sieber@tum.de.
authors.forename: Stephan A
authors.initials: SA
authors.lastname: Sieber
mesh_terms: D000444:Aldehyde Dehydrogenase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000080924:Aldehyde Dehydrogenase 1 Family; D000903:Antibiotics, Antineoplastic / Q000737:chemistry / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D000080890:Duocarmycins; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology*; D056004:Molecular Dynamics Simulation; D015394:Molecular Structure; D011760:Pyrrolidinones / Q000737:chemistry / Q000494:pharmacology; D050697:Retinal Dehydrogenase; D013329:Structure-Activity Relationship
chemical_list: D000903:Antibiotics, Antineoplastic; D000080890:Duocarmycins; D004791:Enzyme Inhibitors; D007211:Indoles; D011760:Pyrrolidinones; D000080924:Aldehyde Dehydrogenase 1 Family; D000444:Aldehyde Dehydrogenase; C510223:ALDH1A1 protein, human; D050697:Retinal Dehydrogenase; C058289:duocarmycin A
keywords: ALDH1A1; duocarmycin; enzymes; inhibitors; protein structure