4L1O

Crystal structure of human ALDH3A1 with inhibitor 1-{[4-(1,3-benzodioxol-5-ylmethyl)piperazin-1-yl]methyl}-1H-indole-2,3-dione

Summary for 4L1O

• Entry DOI: 10.2210/pdb4l1o/pdb
• Related: 3SZA 3SZB 4L2O
• Descriptor: Aldehyde dehydrogenase, (3S)-1-{[4-(1,3-benzodioxol-5-ylmethyl)piperazin-1-yl]methyl}-3-hydroxy-1,3-dihydro-2H-indol-2-one, POTASSIUM ION, ... (5 entities in total)
• Functional Keywords: catalyzes benzaldehyde, rossmann fold, dehydrogenase, nadp+ binding, oxidoreductase-inhibitor complex, oxidoreductase/inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm: P30838
• Total number of polymer chains: 2
• Total formula weight: 105528.81

Authors

Hurley, T.D.,Parajuli, B. (deposition date: 2013-06-03, release date: 2014-04-16, Last modification date: 2024-11-27)

Primary citation

Kimble-Hill, A.C.,Parajuli, B.,Chen, C.H.,Mochly-Rosen, D.,Hurley, T.D.
Development of selective inhibitors for aldehyde dehydrogenases based on substituted indole-2,3-diones.
J.Med.Chem., 57:714-722, 2014

PubMed Abstract: Aldehyde dehydrogenases (ALDH) participate in multiple metabolic pathways and have been indicated to play a role in several cancerous disease states. Our laboratory is interested in developing novel and selective ALDH inhibitors. We looked to further work recently published by developing a class of isoenzyme-selective inhibitors using similar indole-2,3-diones that exhibit differential inhibition of ALDH1A1, ALDH2, and ALDH3A1. Kinetic and X-ray crystallography data suggest that these inhibitors are competitive against aldehyde binding, forming direct interactions with active-site cysteine residues. The selectivity is precise in that these compounds appear to interact directly with the catalytic nucleophile, Cys243, in ALDH3A1 but not in ALDH2. In ALDH2, the 3-keto group is surrounded by the adjacent Cys301/303. Surprisingly, the orientation of the interaction changes depending on the nature of the substitutions on the basic indole ring structure and correlates well with the observed structure-activity relationships for each ALDH isoenzyme.

PubMed: 24444054
DOI: 10.1021/jm401377v

Experimental method

X-RAY DIFFRACTION (2.3 Å)