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| Title | Structure of Mycobacterial NDH-2 Bound to a 2-Mercapto-Quinazolinone Inhibitor. |
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| Journal, issue, pages | J Med Chem, Vol. 68, Issue 7, Page 7579-7591, Year 2025 |
| Publish date | Apr 10, 2025 |
 Authors | Yingke Liang / Stephanie A Bueler / Gregory M Cook / John L Rubinstein /    |
| 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. ...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. |
 External links | J Med Chem / PubMed:40117195 |
| Methods | EM (single particle) |
| Resolution | 3.0 Å |
| Structure data | EMDB-48544, PDB-9mqy: EMDB-48546, PDB-9mqz: |
| Chemicals |  ChemComp-FAD:  PDB-1bnr: |
| Source |
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 Keywords | MEMBRANE PROTEIN / flavoprotein / oxidoreductase / electron transport / metabolism |
mycolicibacterium smegmatis mc2 155 (bacteria)