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J Am Chem Soc. 2018 May 30;140(21):6518-6521. doi: 10.1021/jacs.8b02100. Epub 2018 May 18.

Structure-Function Analysis of the Extended Conformation of a Polyketide Synthase Module.

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Department of Pharmaceutical Chemistry , University of California San Francisco , San Francisco , California 94158 , United States.
Stanford Synchrotron Radiation Lightsource, SLAC National Accelerator Laboratory , Stanford University , Menlo Park , California 94025 , United States.
Department of Chemistry , Box H, Brown University , Providence , Rhode Island 02912-9108 , United States.


Catalytic modules of assembly-line polyketide synthases (PKSs) have previously been observed in two very different conformations-an "extended" architecture and an "arch-shaped" architecture-although the catalytic relevance of neither has been directly established. By the use of a fully human naïve antigen-binding fragment (Fab) library, a high-affinity antibody was identified that bound to the extended conformation of a PKS module, as verified by X-ray crystallography and tandem size-exclusion chromatography-small-angle X-ray scattering (SEC-SAXS). Kinetic analysis proved that this antibody-stabilized module conformation was fully competent for catalysis of intermodular polyketide chain translocation as well as intramodular polyketide chain elongation and functional group modification of a growing polyketide chain. Thus, the extended conformation of a PKS module is fully competent for all of its essential catalytic functions.

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