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Structural basis for hijacking siderophore receptors by antimicrobial lasso peptides


The lasso peptide microcin J25 is known to hijack the siderophore receptor FhuA for initiating internalization. Here, we provide what is to our knowledge the first structural evidence on the recognition mechanism, and our biochemical data show that another closely related lasso peptide cannot interact with FhuA. Our work provides an explanation on the narrow activity spectrum of lasso peptides and opens the path to the development of new antibacterials.

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Figure 1: Structure of E. coli FhuA in complex with MccJ25.
Figure 2: Interaction studies of lasso peptides with FhuA by phage T5 infection and non-denaturing MS.

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We are grateful to P. Boulanger (Institute of Biochemistry and Molecular and Cellular Biophysics, Orsay University) for her kind gift of phage T5. We would like to thank the Diamond Light Source for beam time allocation and access. We thank the MS platform at the Muséum national d'Histoire naturelle for access to the spectrometers, together with K.-P. Yan and Z. Falk for contributing to the site-directed mutagenesis and phage competition experiments, respectively. The Oxford University Mass Spectrometry facility is funded by the Medical Research Council (DNRUBH0 to C.V.R.). M.P.L. is funded by the Wellcome Trust (WT/099165/Z/12/Z to S. Iwata). I.M. is supported by a Ministry of Science, Technology and Innovation postgraduate scholarship. Part of this work was supported by the Biotechnology and Biological Sciences Research Council (BB/H01778X/1 to K.B.).

Author information




I.M. and S.Z. contributed equally to this work. S.R. and K.B. designed and managed the overall project. I.M. and K.B. grew crystals, collected data, and built and refined the structure. H.G.C. purified protein for ligand binding studies. All of the authors analyzed the structure. S.Z and Y.L. designed MccJ25 variants, and performed T5 competition and antibacterial assays. C.G. produced and purified peptides. S.M. and C.V.R. performed MS measurements and analysis. S.R. and K.B. wrote the manuscript with help from the other authors.

Corresponding authors

Correspondence to Sylvie Rebuffat or Konstantinos Beis.

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The authors declare no competing financial interests.

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Supplementary Results, Supplementary Tables 1–5 and Supplementary Figures 1–12. (PDF 14897 kb)

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Mathavan, I., Zirah, S., Mehmood, S. et al. Structural basis for hijacking siderophore receptors by antimicrobial lasso peptides. Nat Chem Biol 10, 340–342 (2014).

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