5L3Z

polyketide ketoreductase SimC7 - binary complex with NADP+

Summary for 5L3Z

• Entry DOI: 10.2210/pdb5l3z/pdb
• Descriptor: polyketide ketoreductase SimC7, NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE (3 entities in total)
• Functional Keywords: short-chain dehydrogenase/reductase, ketoreductase, simocyclinone, dna gyrase inhibitor, oxidoreductase
• Biological source: Streptomyces antibioticus
• Total number of polymer chains: 1
• Total formula weight: 33020.99

Authors

Schafer, M.,Stevenson, C.E.M.,Wilkinson, B.,Lawson, D.M.,Buttner, M.J. (deposition date: 2016-05-24, release date: 2016-10-05, Last modification date: 2024-11-13)

Primary citation

Schafer, M.,Stevenson, C.E.,Wilkinson, B.,Lawson, D.M.,Buttner, M.J.
Substrate-Assisted Catalysis in Polyketide Reduction Proceeds via a Phenolate Intermediate.
Cell Chem Biol, 23:1091-1097, 2016

PubMed Abstract: SimC7 is a polyketide ketoreductase involved in biosynthesis of the angucyclinone moiety of the gyrase inhibitor simocyclinone D8 (SD8). SimC7, which belongs to the short-chain dehydrogenase/reductase (SDR) superfamily, catalyzes reduction of the C-7 carbonyl of the angucyclinone, and the resulting hydroxyl is essential for antibiotic activity. SimC7 shares little sequence similarity with characterized ketoreductases, suggesting it might have a distinct mechanism. To investigate this possibility, we determined the structures of SimC7 alone, with NADP(+), and with NADP(+) and the substrate 7-oxo-SD8. These structures show that SimC7 is distinct from previously characterized polyketide ketoreductases, lacking the conserved catalytic triad, including the active-site tyrosine that acts as central acid-base catalyst in canonical SDR proteins. Taken together with functional analyses of active-site mutants, our data suggest that SimC7 catalyzes a substrate-assisted, two-step reaction for reduction of the C-7 carbonyl group involving intramolecular transfer of a substrate-derived proton to generate a phenolate intermediate.

PubMed: 27617849
DOI: 10.1016/j.chembiol.2016.07.018

Experimental method

X-RAY DIFFRACTION (1.95 Å)