Pyridomycin bridges the NADH- and substrate-binding pockets of the enoyl reductase InhA.
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Hartkoorn RC, Pojer F, Read JA, Gingell H, Neres J, Horlacher OP, Altmann KH, Cole ST
Pyridomycin bridges the NADH- and substrate-binding pockets of the enoyl reductase InhA.
Nat Chem Biol. 2014 Feb;10(2):96-8. doi: 10.1038/nchembio.1405. Epub 2013 Dec 1.
- PubMed ID
- 24292073 [ View in PubMed]
- Abstract
Pyridomycin, a natural product with potent antituberculosis activity, inhibits a major drug target, the InhA enoyl reductase. Here, we unveil the co-crystal structure and unique ability of pyridomycin to block both the NADH cofactor- and lipid substrate-binding pockets of InhA. This is to our knowledge a first-of-a-kind binding mode that discloses a new means of InhA inhibition. Proof-of-principle studies show how structure-assisted drug design can improve the activity of new pyridomycin derivatives.