Structural studies of Mycobacterium tuberculosis DprE1 interacting with its inhibitors.
The flavoenzyme DprE1 catalyses a crucial step in arabinan production for cell wall biosynthesis in Mycobacterium tuberculosis and is a highly vulnerable drug target. It was first discovered using benzothiazinones (BTZ): exquisitely potent bactericidal agents that are being developed as drugs to treat tuberculosis. Subsequently, many compounds with diverse scaffolds were found to act as either covalent or noncovalent DprE1 inhibitors. Covalent inhibitors, like the BTZ, are all nitroaromatic compounds that serve as suicide substrates after DprE1-mediated nitroreduction. Here, we describe how high-resolution structures of DprE1, alone and in complex with various ligands, explain enzyme activity and inhibition.
Global Health Institute, Ecole Polytechnique Fédérale de Lausanne, Station 19, 1015 Lausanne, Switzerland.
Jérémie
J
Piton
Global Health Institute, Ecole Polytechnique Fédérale de Lausanne, Station 19, 1015 Lausanne, Switzerland.
Caroline S-Y
CS
Foo
Global Health Institute, Ecole Polytechnique Fédérale de Lausanne, Station 19, 1015 Lausanne, Switzerland. Electronic address: stewart.cole@epfl.ch.
Stewart T
ST
Cole
D000429:Alcohol Oxidoreductases / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D000818:Animals; D000995:Antitubercular Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000378:metabolism; D011487:Protein Conformation; D014376:Tuberculosis / Q000188:drug therapy
D000995:Antitubercular Agents; D001426:Bacterial Proteins; D000429:Alcohol Oxidoreductases; C583625:DprE1 protein, Mycobacterium tuberculosis