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Pyridomycin bridges the NADH- and substrate-binding pockets of the enoyl reductase InhA

Nature Chemical Biology volume 10, pages 96–98 (2014)Cite this article

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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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Figure 1: Mechanism of action of pyridomycin.
Figure 2: Architecture of the pyridomycin-binding site and critical contacts.
Figure 3: Comparison of the binding pockets of various InhA inhibitors.

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Acknowledgements

The authors would like to thank S. Surade (University of Cambridge) for providing the InhA expression plasmid (pIH51), S. Boy-Röttger and G. Cuanoud (both from EPFL) for technical assistance and G. Shiek (AstraZeneca) for protein supply. The research leading to these results received funding from the European Community's Seventh Framework Programme (grant 260872). J. Neres is the recipient of a Marie Curie fellowship from the European Commission.

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Authors and Affiliations

  1. Ecole Polytechnique Fédérale de Lausanne, Global Health Institute, Lausanne, Switzerland

    Ruben C Hartkoorn, Florence Pojer, João Neres & Stewart T Cole

  2. Discovery Sciences, Innovative Medicines, AstraZeneca, Cheshire, UK

    Jon A Read & Helen Gingell

  3. Swiss Federal Institute of Technology (ETH) Zürich, Institute of Pharmaceutical Sciences, Zürich, Switzerland

    Oliver P Horlacher & Karl-Heinz Altmann

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  1. Ruben C Hartkoorn
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  8. Stewart T Cole
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Contributions

R.C.H., F.P., J.A.R., H.G., J.N. and O.P.H. designed the experiments. R.C.H., F.P., J.A.R., H.G. and J.N. performed the experiments. R.C.H., F.P., J.A.R. and J.N. analyzed data. K.-H.A. and O.P.H. contributed reagents. R.C.H., F.P., J.A.R., J.N. and S.T.C. wrote the paper.

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Correspondence to Stewart T Cole.

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R.C.H., O.P.H., K.-H.A. and S.T.C. are named inventors on patents relating to this work.

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Supplementary Results, Supplementary Table 1 and Supplementary Figures 1–3. (PDF 1091 kb)

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Hartkoorn, R., Pojer, F., Read, J. et al. Pyridomycin bridges the NADH- and substrate-binding pockets of the enoyl reductase InhA. Nat Chem Biol 10, 96–98 (2014). https://doi.org/10.1038/nchembio.1405

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