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1dxo
From Proteopedia
| 1dxo, resolution 2.50Å () | |||||||||
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| Sites: | , , , , , , and | ||||||||
| Ligands: | , | ||||||||
| Activity: | NAD(P)H dehydrogenase (quinone), with EC number 1.6.5.2 | ||||||||
| Related: | 1dxq, 1d4a | ||||||||
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| Resources: | FirstGlance, OCA, PDBsum, RCSB | ||||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||||
CRYSTAL STRUCTURE OF HUMAN NAD[P]H-QUINONE OXIDOREDUCTASE CO WITH 2,3,5,6,TETRAMETHYL-P-BENZOQUINONE (DUROQUINONE) AT 2.5 ANGSTROM RESOLUTION
(see also NADH quinone oxidoreductase (NQO1) with inhibitor dicoumarol)
NAD(P)H/quinone acceptor oxidoreductase (QR1, NQO1, formerly DT-diaphorase; EC ) protects animal cells from the deleterious and carcinogenic effects of quinones and other electrophiles. In this paper we report the apoenzyme structures of human (at 1.7-A resolution) and mouse (2.8 A) QR1 and the complex of the human enzyme with the substrate duroquinone (2.5 A) (2,3,5, 6-tetramethyl-p-benzoquinone). In addition to providing a description and rationale of the structural and catalytic differences among several species, these structures reveal the changes that accompany substrate or cofactor (NAD) binding and release. Tyrosine-128 and the loop spanning residues 232-236 close the binding site, partially occupying the space left vacant by the departing molecule (substrate or cofactor). These changes highlight the exquisite control of access to the catalytic site that is required by the ping-pong mechanism in which, after reducing the flavin, NAD(P)(+) leaves the catalytic site and allows substrate to bind at the vacated position. In the human QR1-duroquinone structure one ring carbon is significantly closer to the flavin N5, suggesting a direct hydride transfer to this atom.
Structures of recombinant human and mouse NAD(P)H:quinone oxidoreductases: species comparison and structural changes with substrate binding and release., Faig M, Bianchet MA, Talalay P, Chen S, Winski S, Ross D, Amzel LM, Proc Natl Acad Sci U S A. 2000 Mar 28;97(7):3177-82. PMID:10706635
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
of the active site of dicoumarol/hNQO1 complex (residues important for ligand interactions are in stick representation and colored magenta, 2f1o) 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.
About this Structure
1DXO is a 4 chains structure of sequences from Homo sapiens. Full crystallographic information is available from OCA.
References
- Faig M, Bianchet MA, Talalay P, Chen S, Winski S, Ross D, Amzel LM. Structures of recombinant human and mouse NAD(P)H:quinone oxidoreductases: species comparison and structural changes with substrate binding and release. Proc Natl Acad Sci U S A. 2000 Mar 28;97(7):3177-82. PMID:10706635 doi:10.1073/pnas.050585797
- 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. 2006 May 23;45(20):6372-8. PMID:16700548 doi:10.1021/bi0600087
Page seeded by OCA on Tue Feb 17 23:50:44 2009
