3SZ9
Crystal structure of human ALDH2 modified with the beta-elimination product of Aldi-3; 1-(4-ethylbenzene)prop-2-en-1-one
Summary for 3SZ9
| Entry DOI | 10.2210/pdb3sz9/pdb |
| Related | 3SZA 3SZB |
| Descriptor | Aldehyde dehydrogenase, mitochondrial, SODIUM ION, GUANIDINE, ... (6 entities in total) |
| Functional Keywords | aldh, aldi-3, inhibitor, rossmann fold, oxidoreductase, covalent adduct, mitochondria, oxidoreductase-oxidoreductase inhibitor complex, oxidoreductase/oxidoreductase inhibitor |
| Biological source | Homo sapiens (human) |
| Cellular location | Mitochondrion matrix: P05091 |
| Total number of polymer chains | 8 |
| Total formula weight | 439845.46 |
| Authors | Perez-Miller, S.,Hurley, T.D. (deposition date: 2011-07-18, release date: 2011-11-02, Last modification date: 2024-11-06) |
| Primary citation | Khanna, M.,Chen, C.H.,Kimble-Hill, A.,Parajuli, B.,Perez-Miller, S.,Baskaran, S.,Kim, J.,Dria, K.,Vasiliou, V.,Mochly-Rosen, D.,Hurley, T.D. Discovery of a novel class of covalent inhibitor for aldehyde dehydrogenases. J.Biol.Chem., 286:43486-43494, 2011 Cited by PubMed Abstract: Human aldehyde dehydrogenases (ALDHs) comprise a family of 17 homologous enzymes that metabolize different biogenic and exogenic aldehydes. To date, there are relatively few general ALDH inhibitors that can be used to probe the contribution of this class of enzymes to particular metabolic pathways. Here, we report the discovery of a general class of ALDH inhibitors with a common mechanism of action. The combined data from kinetic studies, mass spectrometric measurements, and crystallographic analyses demonstrate that these inhibitors undergo an enzyme-mediated β-elimination reaction generating a vinyl ketone intermediate that covalently modifies the active site cysteine residue present in these enzymes. The studies described here can provide the basis for rational approach to design ALDH isoenzyme-specific inhibitors as research tools and perhaps as drugs, to address diseases such as cancer where increased ALDH activity is associated with a cellular phenotype. PubMed: 22021038DOI: 10.1074/jbc.M111.293597 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.1 Å) |
Structure validation
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