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

Jesko Alexander Johannes Gunter Koehnke, Greg Mann, Andrew Frank Bent, Hannes Ludewig, Sally Lorna Shirran, Catherine Helen Botting, Tomas Lebl, Wael Houssen, Marcel Jaspers, Jim Naismith

Research output: Contribution to journalArticlepeer-review

133 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 β-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
Issue number8
Early online date22 Jun 2015
Publication statusPublished - Aug 2015


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