2F1O

Crystal Structure of NQO1 with Dicoumarol

Summary for 2F1O

• Entry DOI: 10.2210/pdb2f1o/pdb
• Descriptor: NAD(P)H dehydrogenase [quinone] 1, BISHYDROXY[2H-1-BENZOPYRAN-2-ONE,1,2-BENZOPYRONE], FLAVIN-ADENINE DINUCLEOTIDE, ... (4 entities in total)
• Functional Keywords: protein inhibitor, structural genomics, israel structural proteomics center, ispc, oxidoreductase, oxidoreductase-inhibitor complex, oxidoreductase/inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm: P15559
• Total number of polymer chains: 8
• Total formula weight: 255186.06

Authors

Shaul, Y.,Asher, G.,Dym, O.,Tsvetkov, P.,Adler, J.,Israel Structural Proteomics Center (ISPC) (deposition date: 2005-11-15, release date: 2006-05-16, Last modification date: 2023-08-23)

Primary citation

Asher, G.,Dym, O.,Tsvetkov, P.,Adler, J.,Shaul, Y.
The crystal structure of NAD(P)H quinone oxidoreductase 1 in complex with its potent inhibitor dicoumarol.
Biochemistry, 45:6372-6378, 2006

PubMed Abstract: NAD(P)H quinone oxidoreductase 1 (NQO1) is a ubiquitous flavoenzyme that catalyzes two-electron reduction of quinones to hydroquinones utilizing NAD(P)H as an electron donor. NQO1 binds and stabilizes several short-lived proteins including the tumor suppressors p53 and p73 and the enzyme ornithine decarboxylase (ODC). Dicoumarol is a widely used potent competitive inhibitor of NQO1 enzymatic activity, which competes with NAD(P)H for binding to NQO1. Dicoumarol also disrupts the binding of NQO1 to p53, p73, and ODC and induces their ubiquitin-independent proteasomal degradation. We report here the crystal structure of human NQO1 in complex with dicoumarol at 2.75 A resolution. We have identified the interactions of dicoumarol with the different residues of NQO1 and the conformational changes imposed upon dicoumarol binding. The most prominent conformational changes that occur in the presence of dicoumarol involve Tyr 128 and Phe 232 that are present on the surface of the NQO1 catalytic pocket. On the basis of the comparison of the NQO1 structure in complex with different NQO1 inhibitors and our previous analysis of NQO1 mutants, we propose that the specific conformation of Tyr 128 and Phe 232 is important for NQO1 interaction with p53 and other client proteins.

PubMed: 16700548
DOI: 10.1021/bi0600087

Experimental method

X-RAY DIFFRACTION (2.75 Å)