Structural insights into xenobiotic and inhibitor binding to human aldehyde oxidase
| Autor: | Catarina Coelho, Maria João Romão, Tobias Hartmann, Teresa Santos-Silva, Silke Leimkühler, Alessandro Foti |
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| Rok vydání: | 2015 |
| Předmět: |
Models
Molecular Protein Conformation Stereochemistry Plasma protein binding Crystallography X-Ray Substrate Specificity Xenobiotics Mice chemistry.chemical_compound Non-competitive inhibition Species Specificity Oxidoreductase Catalytic Domain Escherichia coli Animals Humans Enzyme Inhibitors Xanthine oxidase Molecular Biology Aldehyde oxidase Institut für Biochemie und Biologie chemistry.chemical_classification biology Active site Substrate (chemistry) Cell Biology Aldehyde Oxidoreductases Aldehyde Oxidase Enzyme Biochemistry chemistry biology.protein Protein Binding |
| Zdroj: | Nature Chemical Biology. 11:779-783 |
| ISSN: | 1552-4469 1552-4450 |
| Popis: | Aldehyde oxidase (AOX) is a xanthine oxidase (XO)-related enzyme with emerging importance due to its role in the metabolism of drugs and xenobiotics. We report the first crystal structures of human AOX1, substrate free (2.6-angstrom resolution) and in complex with the substrate phthalazine and the inhibitor thioridazine (2.7-angstrom resolution). Analysis of the protein active site combined with steady-state kinetic studies highlight the unique features, including binding and substrate orientation at the active site, that characterize human AOX1 as an important drug-metabolizing enzyme. Structural analysis of the complex with the noncompetitive inhibitor thioridazine revealed a new, unexpected and fully occupied inhibitor-binding site that is structurally conserved among mammalian AOXs and XO. The new structural insights into the catalytic and inhibition mechanisms of human AOX that we now report will be of great value for the rational analysis of clinical drug interactions involving inhibition of AOX1 and for the prediction and design of AOX-stable putative drugs. |
| Databáze: | OpenAIRE |
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