Structure of the NDH-2 - HQNO inhibited complex provides molecular insight into quinone-binding site inhibitors. ...
Elsevier BV, 2018
academicJournal
Zugriff:
Type II NADH:quinone oxidoreductase (NDH-2) is a proposed drug-target of major pathogenic microorganisms such as Mycobacterium tuberculosis and Plasmodium falciparum. Many NDH-2 inhibitors have been identified, but rational drug development is impeded by the lack of information regarding their mode of action and associated inhibitor-bound NDH-2 structure. We have determined the crystal structure of NDH-2 complexed with a quinolone inhibitor 2-heptyl-4-hydroxyquinoline-N-oxide (HQNO). HQNO is nested into the slot-shaped tunnel of the Q-site, in which the quinone-head group is clamped by Q317 and I379 residues, and hydrogen-bonds to FAD. The interaction of HQNO with bacterial NDH-2 is very similar to the native substrate ubiquinone (UQ1) interactions in the yeast Ndi1-UQ1 complex structure, suggesting a conserved mechanism for quinone binding. Further, the structural analysis provided insight how modifications of quinolone scaffolds improve potency (e.g. quinolinyl pyrimidine derivatives) and suggests ...
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Structure of the NDH-2 - HQNO inhibited complex provides molecular insight into quinone-binding site inhibitors. ...
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Autor/in / Beteiligte Person: | Petri, Jessica ; Shimaki, Yosuke ; Jiao, Wanting ; Bridges, Hannah R ; Russell, Euan R ; Parker, Emily J ; Aragão, David ; Cook, Gregory M ; Nakatani, Yoshio |
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Veröffentlichung: | Elsevier BV, 2018 |
Medientyp: | academicJournal |
DOI: | 10.17863/cam.27654 |
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