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Structural basis for chain release from the enacyloxin polyketide synthase

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; Fülöp, Vilmos; Oldham, Neil J.; Tsai, Shiou-Chuan; Challis, Gregory L.; Lewandowski, Józef R.

Authors

Simone Kosol

Angelo Gallo

Daniel Griffiths

Timothy R. Valentic

Joleen Masschelein

Matthew Jenner

Emmanuel L. C. de los Santos

Lucio Manzi

Paulina K. Sydor

Dean Rea

Shanshan Zhou

Vilmos Fülöp

Neil J. Oldham

Shiou-Chuan Tsai

Gregory L. Challis

Józef R. Lewandowski



Abstract

Modular polyketide synthases and nonribosomal peptide synthetases are molecular assembly lines consisting of several multienzyme subunits that undergo dynamic selfassembly 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.

Journal Article Type Article
Publication Date 2019-10
Journal Nature Chemistry
Print ISSN 1755-4330
Electronic ISSN 1755-4349
Publisher Nature Publishing Group
Peer Reviewed Peer Reviewed
Volume 11
Issue 10
Pages 913-923
APA6 Citation Kosol, S., Gallo, A., Griffiths, D., Valentic, T. R., Masschelein, J., Jenner, M., …Lewandowski, J. R. (2019). Structural basis for chain release from the enacyloxin polyketide synthase. Nature Chemistry, 11(10), 913-923. https://doi.org/10.1038/s41557-019-0335-5
DOI https://doi.org/10.1038/s41557-019-0335-5
Keywords General Chemistry; General Chemical Engineering
Publisher URL https://www.nature.com/articles/s41557-019-0335-5

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