Pyridomycin bridges the NADH- and substrate-binding pockets of the enoyl reductase InhA
December 1st, 2013 by Ruben C Hartkoorn
Nature Chemical Biology 10, 96 (2014). doi:10.1038/nchembio.1405
Authors: Ruben C Hartkoorn, Florence Pojer, Jon A Read, Helen Gingell, João Neres, Oliver P Horlacher, Karl-Heinz Altmann & Stewart T Cole
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.