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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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WRAP-Structural-chain-enacyloxin-polyketide-synthase-Challis-2019.pdf - Accepted Version - Requires a PDF viewer. Download (4Mb) | Preview |
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Microsoft Excel (Supplementary File - Raw carbene footprinting data and SLiM-bHD hits from Genebank)
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Official URL: https://doi.org/10.1038/s41557-019-0335-5
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 | ||||||||||||||||||||||||||||||||||||||||||||||||
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| Subjects: | Q Science > QD Chemistry Q Science > QP Physiology |
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| Divisions: | Faculty of Science, Engineering and Medicine > Science > Chemistry Faculty of Science, Engineering and Medicine > Science > Life Sciences (2010- ) |
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| 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: |
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| 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, | ||||||||||||||||||||||||||||||||||||||||||||||||
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