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

Accepted version
Peer-reviewed

Type

Article

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Authors

Petri, Jessica 
Shimaki, Yosuke 
Jiao, Wanting 
Bridges, Hannah R 
Russell, Euan R 

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.

Description

Keywords

Bioenergetics, Electron transport chain, Enzyme-inhibitor complex structure, NDH-2, Quinolinyl pyrimidine, Quinolone, Bacteria, Binding Sites, Crystallography, Drug Design, Hydrogen Bonding, Quinolones, Quinone Reductases, Ubiquinone

Journal Title

Biochim Biophys Acta Bioenerg

Conference Name

Journal ISSN

0005-2728
1879-2650

Volume Title

1859

Publisher

Elsevier BV
Sponsorship
Medical Research Council (MC_U105663141)