7A6Q
Crystal structure of human aldehyde dehydrogenase 1A3 in complex with selective NR6 inhibitor compound
Summary for 7A6Q
| Entry DOI | 10.2210/pdb7a6q/pdb |
| Descriptor | Aldehyde dehydrogenase family 1 member A3, NICOTINAMIDE-ADENINE-DINUCLEOTIDE, 3-(2-phenylimidazo[1,2-a]pyridin-6-yl)benzenecarbonitrile, ... (7 entities in total) |
| Functional Keywords | dehydrogenase isoenzyme aldh1a3 selective inhibitor high grade glioma, oxidoreductase |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 2 |
| Total formula weight | 115156.74 |
| Authors | Gelardi, E.L.M.,Garavaglia, S. (deposition date: 2020-08-26, release date: 2021-02-17, Last modification date: 2024-01-31) |
| Primary citation | Gelardi, E.L.M.,Colombo, G.,Picarazzi, F.,Ferraris, D.M.,Mangione, A.,Petrarolo, G.,Aronica, E.,Rizzi, M.,Mori, M.,La Motta, C.,Garavaglia, S. A Selective Competitive Inhibitor of Aldehyde Dehydrogenase 1A3 Hinders Cancer Cell Growth, Invasiveness and Stemness In Vitro. Cancers (Basel), 13:-, 2021 Cited by PubMed Abstract: Aldehyde dehydrogenase 1A3 (ALDH1A3) belongs to an enzymatic superfamily composed by 19 different isoforms, with a scavenger role, involved in the oxidation of a plethora of aldehydes to the respective carboxylic acids, through a NAD+-dependent reaction. Previous clinical studies highlighted the high expression of ALDH1A3 in cancer stem cells (CSCs) correlated to a higher risk of cancer relapses, chemoresistance and a poor clinical outcome. We report on the structural, biochemical, and cellular characterization of NR6, a new selective ALDH1A3 inhibitor derived from an already published ALDH non-selective inhibitor with cytotoxic activity on glioblastoma and colorectal cancer cells. Crystal structure, through X-Ray analysis, showed that NR6 binds a non-conserved tyrosine residue of ALDH1A3 which drives the selectivity towards this isoform, as supported by computational binding simulations. Moreover, NR6 shows anti-metastatic activity in wound healing and invasion assays and induces the downregulation of cancer stem cell markers. Overall, our work confirms the role of ALDH1A3 as an important target in glioblastoma and colorectal cells and propose NR6 as a promising molecule for future preclinical studies. PubMed: 33478031DOI: 10.3390/cancers13020356 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.95 Å) |
Structure validation
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