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Journal:JBIC:15
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| - | <StructureSection load='VH9.pdb' size=' | + | <StructureSection load='VH9.pdb' size='450' side='right' scene='Journal:JBIC:15/Cv/1' caption=''> |
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=== Potent Inhibition of Dinuclear Zinc(II) Peptidase, an Aminopeptidase from Aeromonas proteolytica, by 8-Quinolinol Derivatives: Inhibitor Design Based on Zn2+ Fluorophores, Kinetic, and X-ray Crystallographic Study === | === Potent Inhibition of Dinuclear Zinc(II) Peptidase, an Aminopeptidase from Aeromonas proteolytica, by 8-Quinolinol Derivatives: Inhibitor Design Based on Zn2+ Fluorophores, Kinetic, and X-ray Crystallographic Study === | ||
| - | <big>Kengo Hanaya, Miho Suetsugu, Shinya Saijo, Ichiro Yamato, and Shin Aoki</big><ref > | + | <big>Kengo Hanaya, Miho Suetsugu, Shinya Saijo, Ichiro Yamato, and Shin Aoki</big> <ref>DOI 10.1007/s00775-012-0873-4</ref> |
<hr/> | <hr/> | ||
<b>Molecular Tour</b><br> | <b>Molecular Tour</b><br> | ||
| - | The selective inhibition of an <scene name='Journal:JBIC:15/Cv/2'>aminopeptidase from Aeromonas proteolytica (AAP)</scene>, a <scene name='Journal:JBIC:15/Cv/3'>dinuclear Zn2+</scene> hydrolase, by <scene name='Journal:JBIC:15/Cv/10'>8-quinolinol (8-hydroxyquinoline, 8-HQ)</scene> derivatives is reported. Based on our findings about 8-HQ-based Zn<sup>2+</sup> fluorophores, it was hypothesized that 8-HQ derivatives have the potential to function as specific inhibitors of Zn<sup>2+</sup> enzymes, especially dinuclear Zn<sup>2+</sup> hydrolases. Inhibitory assays of 8-HQ derivatives against AAP disclosed that the 8-HQ and 5-substituted 8-HQ′s are competitive inhibitors for AAP with inhibition constants (''K''i) of 0.16—29 μM at pH 8.0. <scene name='Journal:JBIC:15/Cv/11'>X-ray crystal structure analysis of an AAP with 8-HQ complex</scene> (1.3 Å resolution) as well as fluorescence titrations of these drugs with AAP confirmed that <scene name='Journal:JBIC:15/Cv/13'>8-hydroxyquinoline binds to AAP in the 'Pyr-out' mode</scene>, in which the <scene name='Journal:JBIC:15/Cv/15'>hydroxide anion of 8-HQ bridges two Zn2+ (Zn1 and Zn2)</scene> in the active site of AAP and the <scene name='Journal:JBIC:15/Cv/17'>nitrogen atom of 8-HQ coordinates to Zn1</scene> (PDB code: [[3vh9]]). | + | The selective inhibition of an <scene name='Journal:JBIC:15/Cv/2'>aminopeptidase from Aeromonas proteolytica (AAP)</scene>, a <scene name='Journal:JBIC:15/Cv/3'>dinuclear Zn2+</scene> hydrolase, by <scene name='Journal:JBIC:15/Cv/10'>8-quinolinol (8-hydroxyquinoline, 8-HQ)</scene> derivatives is reported. Based on our findings about 8-HQ-based Zn<sup>2+</sup> fluorophores, it was hypothesized that 8-HQ derivatives have the potential to function as specific inhibitors of Zn<sup>2+</sup> enzymes, especially dinuclear Zn<sup>2+</sup> hydrolases. Inhibitory assays of 8-HQ derivatives against AAP disclosed that the 8-HQ and 5-substituted 8-HQ′s are competitive inhibitors for AAP with inhibition constants (''K''i) of 0.16—29 μM at pH 8.0. <scene name='Journal:JBIC:15/Cv/11'>X-ray crystal structure analysis of an AAP with 8-HQ complex</scene> (1.3 Å resolution) as well as fluorescence titrations of these drugs with AAP confirmed that <scene name='Journal:JBIC:15/Cv/13'>8-hydroxyquinoline binds to AAP in the 'Pyr-out' mode</scene>, in which the <scene name='Journal:JBIC:15/Cv/15'>hydroxide anion of 8-HQ bridges two Zn2+ (Zn1 and Zn2)</scene> in the active site of AAP and the <scene name='Journal:JBIC:15/Cv/17'>nitrogen atom of 8-HQ coordinates to Zn1</scene> (PDB code: [[3vh9]]). <scene name='Journal:JBIC:15/Cv/18'>Overlap of active site</scene> of <span style="color:lime;background-color:black;font-weight:bold;">free AAP (colored green)</span> containing Zn<sup>2+</sup>-bound <font color='red'><b>water molecule (H2O or OH-; red sphere)</b></font> ([[1rtq]]) bridging two Zn<sup>2+</sup> and <font color='darkmagenta'><b>AAP–8-HQ complex (darkmagenta,</b></font> [[3vh9]]). <font color='magenta'><b>Two Zn<sup>2+</sup> are depicted as magenta spheres</b></font>. |
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| + | '''PDB reference:''' Crystal structure of Aeromonas proteolytica aminopeptidase complexed with 8-quinolinol, [[3vh9]]. | ||
</StructureSection> | </StructureSection> | ||
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<references/> | <references/> | ||
__NOEDITSECTION__ | __NOEDITSECTION__ | ||
Current revision
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- ↑ Hanaya K, Suetsugu M, Saijo S, Yamato I, Aoki S. Potent inhibition of dinuclear zinc(II) peptidase, an aminopeptidase from Aeromonas proteolytica, by 8-quinolinol derivatives: inhibitor design based on Zn(2+) fluorophores, kinetic, and X-ray crystallographic study. J Biol Inorg Chem. 2012 Feb 5. PMID:22311113 doi:10.1007/s00775-012-0873-4
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