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Biochim Biophys Acta Bioenerg. 2018 Jul;1859(7):482-490. doi: 10.1016/j.bbabio.2018.03.014. Epub 2018 Apr 3.

Structure of the NDH-2 - HQNO inhibited complex provides molecular insight into quinone-binding site inhibitors.

Author information

1
Department of Microbiology and Immunology, University of Otago, Dunedin 9054, New Zealand.
2
Maurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland, Private Bag 92019, Auckland 1042, New Zealand; Maurice Wilkins Centre for Molecular Biodiscovery, Biomolecular Interaction Centre, University of Canterbury, Christchurch, New Zealand; Ferrier Research Institute, Victoria University of Wellington, Wellington, New Zealand.
3
MRC Mitochondrial Biology Unit, Wellcome Trust/MRC Building, Hills Road, Cambridge CB2 0XY, UK.
4
Australian Synchrotron, 800 Blackburn Road, Clayton, Victoria, VIC3168, Australia.
5
Department of Microbiology and Immunology, University of Otago, Dunedin 9054, New Zealand; Maurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland, Private Bag 92019, Auckland 1042, New Zealand. Electronic address: gregory.cook@otago.ac.nz.
6
Department of Microbiology and Immunology, University of Otago, Dunedin 9054, New Zealand; Maurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland, Private Bag 92019, Auckland 1042, New Zealand. Electronic address: yoshio.nakatani@otago.ac.nz.

Abstract

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 unexplored target space for the rational design of new NDH-2 inhibitors.

KEYWORDS:

Bioenergetics; Electron transport chain; Enzyme-inhibitor complex structure; NDH-2; Quinolinyl pyrimidine; Quinolone

PMID:
29621505
PMCID:
PMC6167311
DOI:
10.1016/j.bbabio.2018.03.014
[Indexed for MEDLINE]
Free PMC Article

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