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Mechanism of intersubunit ketosynthase–dehydratase interaction in polyketide synthases

Jenner, Matthew; Kosol, Simone; Griffiths, Daniel; Prasongpholchai, Panward; Manzi, Lucio; Barrow, Andrew S.; Moses, John E.; Oldham, Neil J.; Lewandowski, Jozef; Challis, Gregory


Matthew Jenner

Simone Kosol

Daniel Griffiths

Panward Prasongpholchai

Lucio Manzi

Andrew S. Barrow

John E. Moses

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Professor of Biomolecular Spectrometry

Jozef Lewandowski

Gregory Challis


Modular polyketide synthases (PKSs) produce numerous structurally complex natural products with diverse applications in medicine and agriculture. They typically consist of several multienzyme subunits that utilize structurally-defined docking domains (DDs) at their N- and C-termini to ensure correct assembly into functional multi-protein complexes. Here we report a fundamentally different mechanism for subunit assembly in trans-AT modular PKSs at the junction between ketosynthase (KS) and dehydratase (DH) domains. This involves direct interaction of a largely unstructured docking domain (DD) at the C-terminus of the KS with the surface of the downstream DH. Acyl transfer assays and mechanism-based cross-linking established that the DD is required for the KS to communicate with the acyl carrier protein appended to the DH. Two distinct regions for binding of the DD to the DH were identified using NMR spectroscopy, carbene foot-printing and mutagenesis, providing a foundation for future elucidation of the molecular basis for interaction specificity.


Jenner, M., Kosol, S., Griffiths, D., Prasongpholchai, P., Manzi, L., Barrow, A. S., …Challis, G. (2018). Mechanism of intersubunit ketosynthase–dehydratase interaction in polyketide synthases. Nature Chemical Biology, 14, 270-275.

Journal Article Type Article
Acceptance Date Nov 15, 2017
Online Publication Date Jan 8, 2018
Publication Date 2018-03
Deposit Date Feb 16, 2018
Publicly Available Date Jul 9, 2018
Journal Nature Chemical Biology
Print ISSN 1552-4450
Electronic ISSN 1552-4469
Publisher Nature Publishing Group
Peer Reviewed Peer Reviewed
Volume 14
Pages 270-275
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