Structural analysis of leader peptide binding enables leader-free cyanobactin processing
MetadataShow full item record
Regioselective modification of amino acids within the context of a peptide is common to a number of biosynthetic pathways and many such 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 conserved N-terminal leader for full activity. Catalysis is almost insensitive to immediately flanking residues in the substrate suggesting recognition occurs distant from the active site. Nucleotide and peptide substrate co-complex structures of LynD reveal the substrate leader peptide binds to and extends the β-sheet of a conserved domain of LynD, whilst catalysis is accomplished in another conserved domain. The spatial segregation of catalysis from recognition combines seemingly contradictory properties of regioselectivity and promiscuity; 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.
Koehnke , J A J G , Mann , G , Bent , A F , Ludewig , H , Shirran , S L , Botting , C H , Lebl , T , Houssen , W , Jaspers , M & Naismith , J 2015 , ' Structural analysis of leader peptide binding enables leader-free cyanobactin processing ' Nature Chemical Biology , vol 11 , no. 8 , pp. 558-563 . DOI: 10.1038/nchembio.1841
Nature Chemical Biology
© 2014. Macmillan Publishers Limited. All rights reserved. NPG Terms of reuse of archived manuscipts applies http://www.nature.com/authors/policies/license.html
This work was supported by grants from the ERC 339367 (J.H.N. and M.J.) and BBSRC BB/K015508/1 (J.H.N and M.J.). We acknowledge use of the Diamond (beamlines I02 and I24) and ESRF (beamline ID29) synchrotrons. JHN is Royal Society Wolfson Merit Award Holder and a 1000 talent scholar of the Chinese Government at Sichuan University.
Items in the St Andrews Research Repository are protected by copyright, with all rights reserved, unless otherwise indicated.