TY  - JOUR
A1  - Coelho, Catarina
A1  - Foti, Alessandro
A1  - Hartmann, Tobias
A1  - Santos-Silva, Teresa
A1  - Leimkühler, Silke
A1  - Romao, Maria Joao
T1  - Structural insights into xenobiotic and inhibitor binding to human aldehyde oxidase
T2  - Nature chemical biology
N2  - 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.
Y1  - 2015
UR  - https://publishup.uni-potsdam.de/frontdoor/index/index/docId/38572
SN  - 1552-4450
SN  - 1552-4469
VL  - 11
IS  - 10
SP  - 779
EP  - +
PB  - Nature Publ. Group
CY  - New York
ER  -