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Structural basis for chain release from the enacyloxin polyketide synthase

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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 ISSN 1755-4330.

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Official URL: https://doi.org/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
Q Science > QP Physiology
Divisions: Faculty of Science, Engineering and Medicine > Science > Chemistry
Faculty of Science, Engineering and Medicine > Science > Life Sciences (2010- )
Library of Congress Subject Headings (LCSH): Polyketides , Nuclear magnetic resonance spectroscopy , Organic solid state chemistry, X-ray crystallography , Carbenes (Methylene compounds), Mass spectrometry
Journal or Publication Title: Nature Chemistry
Publisher: Nature Publishing Group
ISSN: 1755-4330
Official Date: October 2019
Dates:
DateEvent
October 2019Published
23 September 2019Available
19 August 2019Accepted
23 July 2018Submitted
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
Date of first compliant deposit: 22 August 2019
Date of first compliant Open Access: 23 March 2020
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,
RIOXX Funder/Project Grant:
Project/Grant IDRIOXX Funder NameFunder ID
639907Seventh Framework Programmehttp://dx.doi.org/10.13039/100011102
RG130022Royal Societyhttp://dx.doi.org/10.13039/501100000288
EP/L025906/1[EPSRC] Engineering and Physical Sciences Research Councilhttp://dx.doi.org/10.13039/501100000266
BB/L022761/1 [BBSRC] Biotechnology and Biological Sciences Research Councilhttp://dx.doi.org/10.13039/501100000268
BB/R010218/1[BBSRC] Biotechnology and Biological Sciences Research Councilhttp://dx.doi.org/10.13039/501100000268
OPP1160394Bill and Melinda Gates Foundationhttp://dx.doi.org/10.13039/100000865
656067European Commissionhttp://dx.doi.org/10.13039/501100000780
BB/L021692/1 [BBSRC] Biotechnology and Biological Sciences Research Councilhttp://dx.doi.org/10.13039/501100000268
BB/K002341/1[BBSRC] Biotechnology and Biological Sciences Research Councilhttp://dx.doi.org/10.13039/501100000268
WM130033Royal Societyhttp://dx.doi.org/10.13039/501100000288
UNSPECIFIEDUniversity of Warwickhttp://dx.doi.org/10.13039/501100000741
EP/L015307[EPSRC] Engineering and Physical Sciences Research Councilhttp://dx.doi.org/10.13039/501100000266
EP/M027503/1[EPSRC] Engineering and Physical Sciences Research Councilhttp://dx.doi.org/10.13039/501100000266
BB/M017982/1[EPSRC] Engineering and Physical Sciences Research Councilhttp://dx.doi.org/10.13039/501100000266
BB/M017982/1[BBSRC] Biotechnology and Biological Sciences Research Councilhttp://dx.doi.org/10.13039/501100000268
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