title: Pyridomycin bridges the NADH- and substrate-binding pockets of the enoyl reductase InhA.
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.
authors.affiliation: Ecole Polytechnique Fédérale de Lausanne, Global Health Institute, Lausanne, Switzerland.
authors.forename: Ruben C
authors.initials: RC
authors.lastname: Hartkoorn
authors.affiliation: Ecole Polytechnique Fédérale de Lausanne, Global Health Institute, Lausanne, Switzerland.
authors.forename: Florence
authors.initials: F
authors.lastname: Pojer
authors.affiliation: Discovery Sciences, Innovative Medicines, AstraZeneca, Cheshire, UK.
authors.forename: Jon A
authors.initials: JA
authors.lastname: Read
authors.affiliation: Discovery Sciences, Innovative Medicines, AstraZeneca, Cheshire, UK.
authors.forename: Helen
authors.initials: H
authors.lastname: Gingell
authors.affiliation: Ecole Polytechnique Fédérale de Lausanne, Global Health Institute, Lausanne, Switzerland.
authors.forename: João
authors.initials: J
authors.lastname: Neres
authors.affiliation: Swiss Federal Institute of Technology (ETH) Zürich, Institute of Pharmaceutical Sciences, Zürich, Switzerland.
authors.forename: Oliver P
authors.initials: OP
authors.lastname: Horlacher
authors.affiliation: Swiss Federal Institute of Technology (ETH) Zürich, Institute of Pharmaceutical Sciences, Zürich, Switzerland.
authors.forename: Karl-Heinz
authors.initials: KH
authors.lastname: Altmann
authors.affiliation: Ecole Polytechnique Fédérale de Lausanne, Global Health Institute, Lausanne, Switzerland.
authors.forename: Stewart T
authors.initials: ST
authors.lastname: Cole
mesh_terms: D000995:Antitubercular Agents / Q000737:chemistry*; D001426:Bacterial Proteins / Q000737:chemistry*; D001665:Binding Sites; D018360:Crystallography, X-Ray; D008958:Models, Molecular; D009243:NAD / Q000737:chemistry*; D009842:Oligopeptides / Q000737:chemistry*; D010088:Oxidoreductases / Q000737:chemistry*; D013379:Substrate Specificity
chemical_list: D000995:Antitubercular Agents; D001426:Bacterial Proteins; D009842:Oligopeptides; D009243:NAD; D010088:Oxidoreductases; C085257:InhA protein, Mycobacterium; C458999:pyridomycin