4K5R

The 2.0 angstrom crystal structure of MTMOIV, a baeyer-villiger monooxygenase from the mithramycin biosynthetic pathway in streptomyces argillaceus.

Summary for 4K5R

• Entry DOI: 10.2210/pdb4k5r/pdb
• Related: 4K5S
• Descriptor: Oxygenase, FLAVIN-ADENINE DINUCLEOTIDE (3 entities in total)
• Functional Keywords: oxygenase, mithramycin, baeyer-villiger, flavin binding protein, oxidoreductase, rossmann fold, fad binding protein
• Biological source: Streptomyces argillaceus
• Total number of polymer chains: 2
• Total formula weight: 116190.38

Authors

Noinaj, N.,Bosserman, M.A.,Rohr, J.,Buchanan, S.K. (deposition date: 2013-04-15, release date: 2013-10-09, Last modification date: 2024-02-28)

Primary citation

Bosserman, M.A.,Downey, T.,Noinaj, N.,Buchanan, S.K.,Rohr, J.
Molecular Insight into Substrate Recognition and Catalysis of Baeyer-Villiger Monooxygenase MtmOIV, the Key Frame-Modifying Enzyme in the Biosynthesis of Anticancer Agent Mithramycin.
Acs Chem.Biol., 8:2466-2477, 2013

PubMed Abstract: Baeyer-Villiger monooxygenases (BVMOs) have been shown to play key roles for the biosynthesis of important natural products. MtmOIV, a homodimeric FAD- and NADPH-dependent BVMO, catalyzes the key frame-modifying steps of the mithramycin biosynthetic pathway, including an oxidative C-C bond cleavage, by converting its natural substrate premithramycin B into mithramycin DK, the immediate precursor of mithramycin. The drastically improved protein structure of MtmOIV along with the high-resolution structure of MtmOIV in complex with its natural substrate premithramycin B are reported here, revealing previously undetected key residues that are important for substrate recognition and catalysis. Kinetic analyses of selected mutants allowed us to probe the substrate binding pocket of MtmOIV and also to discover the putative NADPH binding site. This is the first substrate-bound structure of MtmOIV providing new insights into substrate recognition and catalysis, which paves the way for the future design of a tailored enzyme for the chemo-enzymatic preparation of novel mithramycin analogues.

PubMed: 23992662
DOI: 10.1021/cb400399b

Experimental method

X-RAY DIFFRACTION (2 Å)