Kosol, Simone, Gallo, Angelo, Griffiths, Daniel, Valentic, Timothy R., Masschelein, Joleen, Jenner, Matthew, de los Santos, Emmanuel L. C., Manzi, Lucio, Sydor, Paulina K., Rea, Dean, Zhou, Shanshan, Füllöp, Vilmos, Oldham, Neil J., Tsai, Shiou-Chuan, Challis, Gregory L. and Lewandowski, Józef R. (2019) Structural basis for chain release from the enacyloxin polyketide synthase. Nature Chemistry, 11 . 913-923 . doi:10.1038/s41557-019-0335-5

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Abstract

Modular polyketide synthases and nonribosomal peptide synthetases are molecular assembly lines consisting of several multienzyme subunits that undergo dynamic self-assembly to form a functional mega-complex. N- and C-terminal docking domains are usually responsible for mediating interactions between subunits. Here we show that communication between two nonribosomal peptide synthetase subunits responsible for chain release from the enacyloxin polyketide synthase, which assembles an antibiotic with promising activity against Acinetobacter baumannii, is mediated by an intrinsically disordered short linear motif and a ß-hairpin docking domain. The structures, interactions and dynamics of these subunits are characterised using several complementary biophysical techniques, providing extensive insights into binding and catalysis. Bioinformatics analyses reveal that short linear motif/ß-hairpin docking domain pairs mediate subunit interactions in numerous nonribosomal peptide and hybrid polyketide-nonribosomal peptide synthetases, including those responsible for assembling several important drugs. Short linear motifs and ß-hairpin docking domains from heterologous systems are shown to interact productively, highlighting the potential of such interfaces as tools for biosynthetic engineering.

Item Type:	Journal Article
Subjects:	Q Science > QD Chemistry
Divisions:	Faculty of Science > Chemistry Faculty of Science > Life Sciences (2010- )
Journal or Publication Title:	Nature Chemistry
Publisher:	Nature Publishing Group
ISSN:	1755-4330
Official Date:	October 2019
Dates:	Date Event October 2019 Published 23 September 2019 Available 19 August 2019 Accepted 23 July 2018 Submitted
Date of first compliant deposit:	22 August 2019
Volume:	11
Page Range:	913-923
DOI:	10.1038/s41557-019-0335-5
Status:	Peer Reviewed
Publication Status:	Published
Access rights to Published version:	Restricted or Subscription Access
Funder:	European Research Council, BBSRC, EPSRC, Royal Society, Gates Foundation
Grant number:	ERC Starting Grant Agreement 639907, BBSRC Grant BB/L022761/1, BB/R010218/1, BB/L021692/1,BB/K002341/1, EPSRC EP/L025906/1, EP/L015307/1 and EP/M027503/1, Royal Society RG130022,
Related URLs:	Publisher Related dataset

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