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A vancomycin photoprobe identifies the histidine kinase VanSsc as a vancomycin receptor

Nature Chemical Biology volume 6, pages 327–329 (2010)Cite this article

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Abstract

Inducible resistance to the glycopeptide antibiotic vancomycin requires expression of vanH, vanA and vanX, controlled by a two-component regulatory system consisting of a receptor histidine kinase, VanS, and a response regulator, VanR. The identity of the VanS receptor ligand has been debated. Using a synthesized vancomycin photoaffinity probe, we show that vancomycin directly binds Streptomyces coelicolor VanS (VanSsc) and this binding is correlated with resistance and required for vanH, vanA and vanX gene expression.

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Figure 1: VPP covalently labels VanS.
Figure 2: VPP binding to VanS correlates with vanH, vanA and vanX gene expression.

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Acknowledgements

We thank R. Epand for technical assistance with isothermal titration calorimetry and G. Saalbach (John Innes Centre Proteomics Facility) for the Orbitrap analysis. D. Kahne and C. Walsh provided helpful analysis of preliminary data. This research is funded in part by a Canadian Institutes of Health Research grant (MT-14981), a Canada Research Chair in Biochemistry (to G.D.W.), Biotechnology and Biological Sciences Research Council of the UK (BBSRC) grant 208/P20040 (to H.-J.H. and M.J.B.) and a grant-in-aid to the John Innes Centre from the BBSRC. H.-J.H. acknowledges support from the Royal Society and the Medical Research Council (UK).

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Authors and Affiliations

  1. M.G. DeGroote Institute for Infectious Disease Research, McMaster University, Hamilton, Ontario, Canada

    Kalinka Koteva, Xiao Dong Wang, Ishac Nazi & Gerard D Wright

  2. Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada

    Kalinka Koteva, Xiao Dong Wang, Ishac Nazi & Gerard D Wright

  3. John Innes Centre, Norwich, UK

    Hee-Jeon Hong, Mike J Naldrett & Mark J Buttner

  4. Department of Biochemistry, University of Cambridge, Cambridge, UK

    Hee-Jeon Hong

  5. Department of Chemistry, McMaster University, Hamilton, Ontario, Canada

    Donald Hughes

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  1. Kalinka Koteva
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  2. Hee-Jeon Hong
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  3. Xiao Dong Wang
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  4. Ishac Nazi
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  5. Donald Hughes
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  6. Mike J Naldrett
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  7. Mark J Buttner
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  8. Gerard D Wright
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Contributions

K.K. synthesized the compounds, performed labeling experiments and prepared the figures. H.-J.H. prepared genetic constructs and performed the gene expression studies. X.D.W. prepared genetic constructs. I.N. prepared genetic constructs and assisted in protein preparation. M.J.B. and G.D.W. designed and analyzed the experiments. D.H. performed the NMR. M.J.N. performed the mass spectrometry. G.D.W. wrote the manuscript, and all authors edited it.

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Correspondence to Gerard D Wright.

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The authors declare no competing financial interests.

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Koteva, K., Hong, HJ., Wang, X. et al. A vancomycin photoprobe identifies the histidine kinase VanSsc as a vancomycin receptor. Nat Chem Biol 6, 327–329 (2010). https://doi.org/10.1038/nchembio.350

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