9MQZ

Structure of mycobacterial NDH2 (type II NADH:quinone oxidoreductase) with 2-mercapto-quinazolinone inhibitor.

This is a non-PDB format compatible entry.

Summary for 9MQZ

• Entry DOI: 10.2210/pdb9mqz/pdb
• EMDB information: 48546
• Descriptor: NADH:ubiquinone reductase (non-electrogenic), FLAVIN-ADENINE DINUCLEOTIDE, N-cyclohexyl-2-[(4-oxo-1,4-dihydroquinazolin-2-yl)sulfanyl]acetamide (3 entities in total)
• Functional Keywords: flavoprotein, oxidoreductase, electron transport, metabolism, membrane protein
• Biological source: Mycolicibacterium smegmatis MC2 155
• Total number of polymer chains: 2
• Total formula weight: 108496.55

Authors

Liang, Y.,Rubinstein, J.L. (deposition date: 2025-01-06, release date: 2025-01-22, Last modification date: 2025-05-28)

Primary citation

Liang, Y.,Bueler, S.A.,Cook, G.M.,Rubinstein, J.L.
Structure of Mycobacterial NDH-2 Bound to a 2-Mercapto-Quinazolinone Inhibitor.
J.Med.Chem., 68:7579-7591, 2025

PubMed Abstract: Mycobacterial type II NADH dehydrogenase (NDH-2) is a promising drug target because of its central role in energy metabolism in and other pathogens, and because it lacks a known mammalian homologue. To facilitate optimization of lead compounds, we used electron cryomicroscopy (cryo-EM) to determine the structure of NDH-2 from , a fast-growing nonpathogenic model for respiration in . The structure shows that active mycobacterial NDH-2 is dimeric, with an arrangement of monomers in the dimer that differs from the arrangement described for other prokaryotic NDH-2 dimers, instead resembling dimers formed by NDH-2 in the eukaryotes and . A structure of the enzyme bound to a 2-mercapto-quinazolinone inhibitor shows that the compound interacts directly with the flavin adenine dinucleotide cofactor, blocking the menaquinone-reducing site. These results reveal structural elements of NDH-2 that could be used to design specific inhibitors of the mycobacterial enzyme.

PubMed: 40117195
DOI: 10.1021/acs.jmedchem.5c00049

Experimental method

ELECTRON MICROSCOPY (3 Å)