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 Cited by 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: 24444054DOI: 10.1021/jm401377v PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.3 Å) |
Structure validation
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