2z3u
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Crystal Structure of Chromopyrrolic Acid Bound Cytochrome P450 StaP (CYP245A1)
OverviewOverview
Staurosporine isolated from Streptomyces sp. TP-A0274 is a member of the, family of indolocarbazole alkaloids that exhibit strong antitumor, activity. A key step in staurosporine biosynthesis is the formation of the, indolocarbazole core by intramolecular C-C bond formation and oxidative, decarboxylation of chromopyrrolic acid (CPA) catalyzed by cytochrome P450, StaP (StaP, CYP245A1). In this study, we report x-ray crystal structures, of CPA-bound and -free forms of StaP. Upon substrate binding, StaP adopts, a more ordered conformation, and conformational rearrangements of residues, in the active site are also observed. Hydrogen-bonding interactions of two, carboxyl groups and T-shaped pi-pi interactions with indole rings hold the, substrate in the substrate-binding cavity with a conformation, perpendicular to the heme plane. Based on the crystal structure of, StaP-CPA complex, we propose that C-C bond formation occurs through an, indole cation radical intermediate that is equivalent to cytochrome c, peroxidase compound I [Sivaraja M, Goodin DB, Smith M, Hoffman BM (1989), Science 245:738-740]. The subsequent oxidative decarboxylation reaction is, also discussed based on the crystal structure. Our crystallographic study, shows the first crystal structures of enzymes involved in formation of the, indolocarbazole core and provides valuable insights into the process of, staurosporine biosynthesis, combinatorial biosynthesis of, indolocarbazoles, and the diversity of cytochrome P450 chemistry.
About this StructureAbout this Structure
2Z3U is a Single protein structure of sequence from Streptomyces cangkringensis with , and as ligands. Full crystallographic information is available from OCA.
ReferenceReference
Crystal structures and catalytic mechanism of cytochrome P450 StaP that produces the indolocarbazole skeleton., Makino M, Sugimoto H, Shiro Y, Asamizu S, Onaka H, Nagano S, Proc Natl Acad Sci U S A. 2007 Jul 10;104(28):11591-6. Epub 2007 Jul 2. PMID:17606921
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