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; F�l�p, Vilmos; Oldham, Neil J.; Tsai, Shiou-Chuan; Challis, Gregory L.; Lewandowski, J�zef R.

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.

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

• Journal Article Type: Article
• Acceptance Date: Aug 19, 2019
• Online Publication Date: Sep 23, 2019
• Publication Date: 2019-10
• Deposit Date: Oct 17, 2019
• Publicly Available Date: Mar 24, 2020
• 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
• DOI: https://doi.org/10.1038/s41557-019-0335-5
• Keywords: General Chemistry; General Chemical Engineering
• Public URL: https://nottingham-repository.worktribe.com/output/2853237
• Publisher URL: https://www.nature.com/articles/s41557-019-0335-5
• Contract Date: Oct 17, 2019