1mn6
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Thioesterase Domain from Picromycin Polyketide Synthase, pH 7.6
OverviewOverview
Modular polyketide synthases (PKSs) synthesize the polyketide cores of, pharmacologically important natural products such as erythromycin and, picromycin. Understanding PKSs at high resolution could present new, opportunities for chemoenzymatic synthesis of complex molecules. The, crystal structures of macrocycle-forming thioesterase (TE) domains from, the picromycin synthase (PICS) and 6-deoxyerythronolide B synthase (DEBS), were determined to 1.8-3.0 A with an R(crys) of 19.2-24.4%, including, three structures of PICS TE (crystallized at pH 7.6, 8.0, and 8.4) and a, second crystal form of DEBS TE. As predicted by the previous work on DEBS, TE [Tsai, S. C., et al. (2001) Proc. Natl. Acad. Sci. U.S.A. 98, 14808-14813], PICS TE contains an open substrate channel and a hydrophobic, dimer interface. Notwithstanding their similarity, the dimer interfaces, and substrate channels of DEBS TE and PICS TE reveal key differences. The, structural basis for the divergent substrate specificities of DEBS TE and, PICS TE is analyzed. The size of the substrate channel increases with, increasing pH, presumably due to electrostatic repulsion in the channel at, elevated pH. Together, these structures support previous predictions that, macrocycle-forming thioesterases from PKSs share the same protein fold, an, open substrate channel, a similar catalytic mechanism, and a hydrophobic, dimer interface. They also provide a basis for the design of enzymes, capable of catalyzing regioselective macrocyclization of natural or, synthetic substrates. A series of high-resolution snapshots of a protein, channel at different pHs is presented alongside analysis of channel, residues, which could help in the redesign of the protein channel, architecture.
About this StructureAbout this Structure
1MN6 is a Single protein structure of sequence from Streptomyces venezuelae. Full crystallographic information is available from OCA.
ReferenceReference
Insights into channel architecture and substrate specificity from crystal structures of two macrocycle-forming thioesterases of modular polyketide synthases., Tsai SC, Lu H, Cane DE, Khosla C, Stroud RM, Biochemistry. 2002 Oct 22;41(42):12598-606. PMID:12379102
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