NADH quinone oxidoreductase (NQO1) with inhibitor dicoumarol: Difference between revisions
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< | <StructureSection load='2f1o.pdb' size='500' frame='true' align='right' scene='2f1o/Com_view/2' > | ||
The crystal structure of human NQO1 in complex with dicoumarol was determined at 2.75 Å resolution ([[2f1o]]). NQO1 is a <scene name='2f1o/Com_view/6'>physiological homodimer</scene> composed of two interlocked monomers. <scene name='2f1o/Com_view/7'>Two catalytic sites</scene> are formed and are present at the dimer interface (<font color='red'><b>FAD is colored red</b></font> and <font color='blue'><b>dicoumarol is colored blue</b></font>). Therefore, each from these two <scene name='2f1o/Active_site/3'>dicoumarol-hNQO1 binding sites</scene> is formed by both monomers. <font color='cyan'><b>Dicoumarol is colored cyan</b></font>, <font color='orange'><b>FAD in orange</b></font>, nitrogens and oxygens are shown in [http://en.wikipedia.org/wiki/CPK_coloring CPK colors]. NQO1 <font color='blueviolet'><b>chain A is colored blueviolet</b></font> and <font color='lime'><b>chain C in lime</b></font>. 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. | The crystal structure of human NQO1 in complex with dicoumarol was determined at 2.75 Å resolution ([[2f1o]]). NQO1 is a <scene name='2f1o/Com_view/6'>physiological homodimer</scene> composed of two interlocked monomers. <scene name='2f1o/Com_view/7'>Two catalytic sites</scene> are formed and are present at the dimer interface (<font color='red'><b>FAD is colored red</b></font> and <font color='blue'><b>dicoumarol is colored blue</b></font>). Therefore, each from these two <scene name='2f1o/Active_site/3'>dicoumarol-hNQO1 binding sites</scene> is formed by both monomers. <font color='cyan'><b>Dicoumarol is colored cyan</b></font>, <font color='orange'><b>FAD in orange</b></font>, nitrogens and oxygens are shown in [http://en.wikipedia.org/wiki/CPK_coloring CPK colors]. NQO1 <font color='blueviolet'><b>chain A is colored blueviolet</b></font> and <font color='lime'><b>chain C in lime</b></font>. 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. | ||
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<scene name='2f1o/Align/8'>Structural comparison</scene> of the active site of <font color='magenta'><b>dicoumarol/hNQO1 complex</b></font> (residues important for ligand interactions are <font color='magenta'><b>colored magenta</b></font>) with that of <font color='blue'><b>apo hNQO1</b></font> dimer ([[1d4a]], residues important for ligand interactions are <font color='blue'><b>colored blue</b></font>) reveals that structural changes associated with dicoumarol binding occur on several residues involving both monomers. <font color='cyan'><b>Dicoumarol is colored in cyan</b></font>; <font color='orange'><b>FAD is colored in orange</b></font>. 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 <scene name='2f1o/Align/9'>distance</scene> between these residues increases from ~5 Å in the <font color='blue'><b>apo hNQO1</b></font> to ~12 Å in the <font color='magenta'><b>dicoumarol/hNQO1 complex</b></font>. | <scene name='2f1o/Align/8'>Structural comparison</scene> of the active site of <font color='magenta'><b>dicoumarol/hNQO1 complex</b></font> (residues important for ligand interactions are <font color='magenta'><b>colored magenta</b></font>) with that of <font color='blue'><b>apo hNQO1</b></font> dimer ([[1d4a]], residues important for ligand interactions are <font color='blue'><b>colored blue</b></font>) reveals that structural changes associated with dicoumarol binding occur on several residues involving both monomers. <font color='cyan'><b>Dicoumarol is colored in cyan</b></font>; <font color='orange'><b>FAD is colored in orange</b></font>. 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 <scene name='2f1o/Align/9'>distance</scene> between these residues increases from ~5 Å in the <font color='blue'><b>apo hNQO1</b></font> to ~12 Å in the <font color='magenta'><b>dicoumarol/hNQO1 complex</b></font>. | ||
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The crystal structure of human <scene name='Nqo1/Nqo1_1/2'>NQO1</scene> in complex with dicoumarol was determine at 2.75 Å resolution. | The crystal structure of human <scene name='Nqo1/Nqo1_1/2'>NQO1</scene> in complex with dicoumarol was determine at 2.75 Å resolution. | ||
NQO1 is a physiological homodimer composed of two interlocked monomers. Each monomer is composed of two domains: a large catalytic domain with α/β fold with flavodoxin topology (residues 1-220) and a small C-terminal domain (residues 221-273). Two catalytic sites are formed and are present at the dimer interface. Two FAD molecules (red) are present; each one is bound to the catalytic domain of each monomer. The dicoumarol molecule (purple) is bound to each of the catalytic sites interacting with FAD and with residues from both monomer.The dicoumarol molecule is bound to each of the catalytic sites interacting with FAD and with residues from both monomers. | NQO1 is a physiological homodimer composed of two interlocked monomers. Each monomer is composed of two domains: a large catalytic domain with α/β fold with flavodoxin topology (residues 1-220) and a small C-terminal domain (residues 221-273). Two catalytic sites are formed and are present at the dimer interface. Two FAD molecules (red) are present; each one is bound to the catalytic domain of each monomer. The dicoumarol molecule (purple) is bound to each of the catalytic sites interacting with FAD and with residues from both monomer.The dicoumarol molecule is bound to each of the catalytic sites interacting with FAD and with residues from both monomers. | ||
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< | The quinone ES936 causes irreversible inhibition of the NQO1. <scene name='2f1o/Align2/5'>Alignment</scene> of the hNQO1 dimer in complex with <font color='red'><b>ES936 (red)</b></font> ([[1kbq]]) with the hNQO1−dicoumarol complex ([[2f1o]]) 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 <scene name='2f1o/Align2/6'>distance</scene> between Tyr 128 and Phe 232 in the hNQO1−ES936 complex is only ~7 Å, while in the hNQO1−dicoumarol complex it is ~12 Å. | ||
</StructureSection> | |||
==Additional Resources== | ==Additional Resources== | ||
