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MraY–antibiotic complex reveals details of tunicamycin mode of action

Nature Chemical Biology volume 13, pages 265–267 (2017)Cite this article

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Abstract

The rapid increase of antibiotic resistance has created an urgent need to develop novel antimicrobial agents. Here we describe the crystal structure of the promising bacterial target phospho-N-acetylmuramoyl–pentapeptide translocase (MraY) in complex with the nucleoside antibiotic tunicamycin. The structure not only reveals the mode of action of several related natural-product antibiotics but also gives an indication on the binding mode of the MraY UDP–MurNAc–pentapeptide and undecaprenyl-phosphate substrates.

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Figure 1: The MraY tunicamycin complex structure.
Figure 2: Comparison of tunicamycin and MD2 binding.

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Acknowledgements

We thank A. Shapiro and J. Bernström for assistance with activity measurements, beamline scientists at ESRF (Grenoble, France) and Diamond Light Source (Didcot, UK) for assistance during data collection, and members of Global Phasing Ltd. for help with STARANISO. We are also grateful to I. Moraes at the Membrane Protein Laboratory, Diamond for providing beamtime and assistance. This work was supported by the European Union under the programme FP7-PEOPLE-2011-ITN NanoMem, project number 317079 (M.E.) and the European Union's Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie agreement No 637295, X-probe (M.E.).

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  1. Jonna K Hakulinen

    Present address: Present address: Division of Structural Studies, MRC Laboratory of Molecular Biology, Cambridge, UK.,

Authors and Affiliations

  1. Discovery Sciences, Innovative Medicines and Early Development Biotech Unit, AstraZeneca R&D Gothenburg, Gothenburg, Sweden

    Jonna K Hakulinen, Jenny Hering, Hongming Chen, Arjan Snijder, Margareta Ek & Patrik Johansson

  2. Department of Chemistry and Molecular Biology, University of Gothenburg, Gothenburg, Sweden

    Jenny Hering & Gisela Brändén

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Contributions

A.S. and M.E. designed the study, J.K.H. established purification and crystallized the protein, J.H. collected and analyzed the activity data, J.K.H. and P.J. collected the crystallographic data, P.J. solved and built the initial model, P.J. and G.B. refined the structure, H.C. performed the docking studies, J.K.H., G.B., M.E. and P.J. prepared the manuscript with input from all authors.

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Correspondence to Margareta Ek or Patrik Johansson.

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Competing interests

J.H., H.C., A.S., M.E. and P.J. are employees of AstraZeneca.

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Supplementary Results, Supplementary Figures 1–8 and Supplementary Tables 1 and 2. (PDF 2748 kb)

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Hakulinen, J., Hering, J., Brändén, G. et al. MraY–antibiotic complex reveals details of tunicamycin mode of action. Nat Chem Biol 13, 265–267 (2017). https://doi.org/10.1038/nchembio.2270

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