4UHW

Human aldehyde oxidase

Summary for 4UHW

• Entry DOI: 10.2210/pdb4uhw/pdb
• Related: 4UHX
• Descriptor: ALDEHYDE OXIDASE, MALONATE ION, FE2/S2 (INORGANIC) CLUSTER, ... (7 entities in total)
• Functional Keywords: oxidoreductase, drug metabolism, molybdenum enzymes, xanthine oxidase enzymes
• Biological source: HOMO SAPIENS (HUMAN)
• Cellular location: Cytoplasm : Q06278
• Total number of polymer chains: 1
• Total formula weight: 149994.15

Authors

Coelho, C.,Romao, M.J.,Santos-Silva, T. (deposition date: 2015-03-26, release date: 2015-09-02, Last modification date: 2024-01-10)

Primary citation

Coelho, C.,Foti, A.,Hartmann, T.,Santos-Silva, T.,Leimkuhler, S.,Romao, M.J.
Structural Insights Into Xenobiotic and Inhibitor Binding to Human Aldehyde Oxidase
Nat.Chem.Biol., 11:779-, 2015

PubMed Abstract: 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-Å resolution) and in complex with the substrate phthalazine and the inhibitor thioridazine (2.7-Å 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.

PubMed: 26322824
DOI: 10.1038/NCHEMBIO.1895

Experimental method

X-RAY DIFFRACTION (2.6 Å)