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2f1o
From Proteopedia
Crystal Structure of NQO1 with Dicoumarol
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.
The crystal structure of NAD(P)H quinone oxidoreductase 1 in complex with its potent inhibitor dicoumarol., Asher G, Dym O, Tsvetkov P, Adler J, Shaul Y, Biochemistry. 2006 May 23;45(20):6372-8. PMID:16700548
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
of the hNQO1 homodimer with FAD (red) and dicoumarol (blue). The . Dicoumarol is colored cyan, FAD in orange, nitrogens and oxygens are shown in CPK colors. NQO1 chain A is colored blueviolet and chain C in lime. NQO1 residues, participating in ligand interactions, are shown as stick representation and are labeled (A and C refer to the NQO1 chains). H-bonds are shown by dashed lines with their distances.
of the active site of dicoumarol/hNQO1 complex (residues important for ligand interactions are in stick representation and colored magenta) with the apo hNQO1 (1d4a, residues important for ligand interactions are colored blue). Dicoumarol is colored in cyan; FAD is colored in orange. The RMSD between the apo hNQO1 (1d4a) and hNQO1 in complex with dicoumarol is 0.36Å for the 546 Cα atoms. The dicoumarol-hNQO1 binding causes several structural changes. The most prominent of them is Tyr 128 and Phe 232 movement in the first monomer. These residues are located on the surface of the NQO1 catalytic pocket. The between these residues increases from ~5 Å in the apo hNQO1 to ~12 Å in the dicoumarol/hNQO1 complex. Quinones (including duroquinone (2,3,5,6-tetramethyl-p-benzoquinone) are substrates of NQO1 (it catalyzes two-electron reduction of them to hydroquinones). Duroquinone (yellow) binds to the by interactions involving the FAD and several hydrophobic and hydrophilic residues in the duroquinone-NQO1 complex (1dxo). The structure of the hNQO1 dimer in complex with duroquinone is also similar to that of hNQO1 in complex with dicoumarol (RMSD is 0.33Å for the 546 Cα atoms). In this case, the main differences between these two structures, as well as to that of apo hNQO1, involve the distance between residues of the first monomer. The FAD molecule has very similar conformation in both hNQO1-duroquinone (pink) and hNQO1−dicoumarol (orange) complexes.
The quinone ES936 causes irreversible inhibition of the NQO1. of the hNQO1 dimer in complex with ES936 (red) (1kbq) with the hNQO1−dicoumarol complex yields 0.45Å RMSD for the 546 Cα atoms. The ES936 causes structural change only in the position of Phe 232. The movement of this residue is smaller than that caused by dicoumarol. The between Tyr 128 and Phe 232 in the hNQO1−ES936 complex is only ~8 Å, while in the hNQO1−dicoumarol complex it is ~12 Å.
About this Structure
2F1O is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.
Reference
The crystal structure of NAD(P)H quinone oxidoreductase 1 in complex with its potent inhibitor dicoumarol., Asher G, Dym O, Tsvetkov P, Adler J, Shaul Y, Biochemistry. 2006 May 23;45(20):6372-8. PMID:16700548
Page seeded by OCA on Mon Oct 20 12:04:02 2008
