Structural analysis of leader peptide binding enables leader-free cyanobactin processing

Jesko Koehnke, Greg Mann, Andrew F. Bent, Hannes Ludewig, Sally Shirran, Catherine Botting, Tomas Lebl, Wael E. Houssen, Marcel Jaspars, James H. Naismith*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

121 Citations (Scopus)


Regioselective modification of amino acids within the context of a peptide is common to a number of biosynthetic pathways, and many of the resulting products have potential as therapeutics. The ATP-dependent enzyme LynD heterocyclizes multiple cysteine residues to thiazolines within a peptide substrate. The enzyme requires the substrate to have a conserved N-terminal leader for full activity. Catalysis is almost insensitive to immediately flanking residues in the substrate, suggesting that -recognition occurs distant from the active site. Nucleotide and peptide substrate co-complex structures of LynD reveal that the substrate leader peptide binds to and extends the beta-sheet of a conserved domain of LynD, whereas catalysis is accomplished in another conserved domain. The spatial segregation of catalysis from recognition combines seemingly contradictory properties of regioselectivity and promiscuity, and it appears to be a conserved strategy in other peptide-modifying enzymes. A variant of LynD that efficiently processes substrates without a leader peptide has been engineered.

Original languageEnglish
Pages (from-to)558-563
Number of pages8
JournalNature Chemical Biology
Early online date22 Jun 2015
Publication statusPublished - Aug 2015

Bibliographical note

This work was supported by grants from the European Research Council (no. 339367, J.H.N. and M.J.), the UK Biotechnology and Biological Sciences Research Council (no. BB/K015508/1, J.H.N. and M.J.) and the Wellcome Trust, which funded the purchase of the TripleTOF 5600 mass spectrometer at the Biomedical Sciences Research Complex Mass Spectrometry and Proteomics Facility, University of St. Andrews (grant no. 094476/Z/10/Z), and the MALDI TOF-TOF Analyser (grant no. WT079272AIA). We acknowledge use of the Diamond (beamlines I02 and I24) and ESRF (beamline ID29) synchrotrons. J.H.N. is a Royal Society Wolfson Merit Award Holder and a 1000 talent scholar of the Chinese Government at Sichuan University.




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