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.
Ruben C Hartkoorn  1 ,  Florence Pojer  1 ,  Jon A Read  2 ,  Helen Gingell  2 ,  João Neres  1 ,  Oliver P Horlacher  3 ,  Karl-Heinz Altmann  3 ,  Stewart T Cole  1
Affiliations
  • 1. Ecole Polytechnique Fédérale de Lausanne, Global Health Institute, Lausanne, Switzerland.
  • 2. Discovery Sciences, Innovative Medicines, AstraZeneca, Cheshire, UK.
  • 3. Swiss Federal Institute of Technology (ETH) Zürich, Institute of Pharmaceutical Sciences, Zürich, Switzerland.
PMID: 24292073 DOI: 10.1038/nchembio.1405
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.

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