Structure and Substrate Recognition of the Bottromycin Maturation Enzyme BotP |
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| Authors: | Greg Mann Dr Liujie Huo Sebastian Adam Dr Brunello Nardone Dr Jeremie Vendome Prof Nicholas James Westwood Prof Rolf Müller Dr Jesko Koehnke |
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| Affiliation: | 1. School of Chemistry and Biomedical Sciences Research Centre, University of St. Andrews, St. Andrews, UK;2. Roger Adams Laboratory 156, University of Illinois at Urbana–Champaign, Urbana, IL, USA;3. Workgroup Structural Biology of Biosynthetic Enzymes, Helmholtz Institute for Pharmaceutical Research, Helmholtz Centre for Infection Research, Saarland University, Saarbrücken, Germany;4. Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY, USA;5. Howard Hughes Medical Institute, Columbia University, New York, NY, USA;6. Department of Microbial Natural Products, Helmholtz Institute for Pharmaceutical Research, Helmholtz Centre for Infection Research, Saarland University, Saarbrücken, Germany |
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| Abstract: | The bottromycins are a family of highly modified peptide natural products, which display potent antimicrobial activity against Gram‐positive bacteria, including methicillin‐resistant Staphylococcus aureus. Bottromycins have recently been shown to be ribosomally synthesized and post‐translationally modified peptides (RiPPs). Unique amongst RiPPs, the precursor peptide BotA contains a C‐terminal “follower” sequence, rather than the canonical N‐terminal “leader” sequence. We report herein the structural and biochemical characterization of BotP, a leucyl‐aminopeptidase‐like enzyme from the bottromycin pathway. We demonstrate that BotP is responsible for the removal of the N‐terminal methionine from the precursor peptide. Determining the crystal structures of both apo BotP and BotP in complex with Mn2+ allowed us to model a BotP/substrate complex and to rationalize substrate recognition. Our data represent the first step towards targeted compound modification to unlock the full antibiotic potential of bottro‐ mycin. |
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| Keywords: | biosynthesis BotP bottromycin leucyl-aminopeptidases RiPPs |
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