Journal
CHEMISTRY & BIOLOGY
Volume 20, Issue 11, Pages 1340-1351Publisher
CELL PRESS
DOI: 10.1016/j.chembiol.2013.09.015
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Funding
- National Institutes of Health [NIH] National Institute of General Medical Sciences [GM, Y1-GM-1104]
- National Cancer Institute [CA] [Y1-CO-1020]
- United States Department of Energy
- Argonne National Laboratory
- Chemical Biology interface training grant
- Rackham Merit and American Foundation for Pharmaceutical Education predoctoral fellowships
- NIH [GM076477, CA108874, DK042303]
- Hans W. Vahlteich Professorship
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Modular type I polyketide synthases (PKSs) are versatile biosynthetic systems that initiate, successively elongate, and modify acyl chains. Intermediate transfer between modules is mediated via docking domains, which are attractive targets for PKS pathway engineering to produce natural product analogs. We identified a class 2 docking domain in cyanobacterial PKSs and determined crystal structures for two docking domain pairs, revealing a distinct class 2 docking strategy for promoting intermediate transfer. The selectivity of class 2 docking interactions, demonstrated in binding and biochemical assays, could be altered by mutagenesis. We determined the ideal fusion location for exchanging class 1 and class 2 docking domains and demonstrated effective polyketide chain transfer in heterologous modules. Thus, class 2 docking domains are tools for rational bioengineering of a broad range of PKSs containing either class 1 or 2 docking domains.
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