8JNO

Crystal structure of cytochrome P450 IkaD from Streptomyces sp. ZJ306, in complex with the substrate 10-epi-deOH-HSAF

Summary for 8JNO

• Entry DOI: 10.2210/pdb8jno/pdb
• Descriptor: Cytochrome P450, PROTOPORPHYRIN IX CONTAINING FE, (1Z,3E,5S,7S,8R,9S,10S,11R,13R,15R,16S,18Z,25S)-11-ethyl-2,7-dihydroxy-10-methyl-21,26-diazapentacyclo[23.2.1.09,13.08,15.05,16]octacosa-1(2),3,18-triene-20,27,28-trione, ... (5 entities in total)
• Functional Keywords: hydroxylation, polycyclic tetramate macrolactam, oxidoreductase, cytochrome p450
• Biological source: Streptomyces sp. ZJ306
• Total number of polymer chains: 2
• Total formula weight: 94023.46

Authors

Zhang, Y.L.,Zhang, L.P.,Zhang, C.S. (deposition date: 2023-06-06, release date: 2023-11-22, Last modification date: 2023-12-20)

Primary citation

Jiang, P.,Jin, H.,Zhang, G.,Zhang, W.,Liu, W.,Zhu, Y.,Zhang, C.,Zhang, L.
A Mechanistic Understanding of the Distinct Regio- and Chemoselectivity of Multifunctional P450s by Structural Comparison of IkaD and CftA Complexed with Common Substrates.
Angew.Chem.Int.Ed.Engl., 62:e202310728-e202310728, 2023

PubMed Abstract: Regio- and chemoselective C-H activation at multi-positions of a single molecule is fascinating but chemically challenging. The homologous cytochrome P450 enzymes IkaD and CftA catalyze multiple C-H oxidations on the same polycyclic tetramate macrolactam (PoTeM) ikarugamycin, with distinct regio- and chemoselectivity. Herein we provide mechanistic understanding of their functional differences by solving crystal structures of IkaD and CftA in complex with ikarugamycin and unnatural substrates. Distinct conformations of the F/G region in IkaD and CftA are found to differentiate the orientation of PoTeM substrates, by causing different binding patterns with polar moieties to determine site selection, oxidation order, and chemoselectivity. Fine-tuning the polar subpocket altered the regioselectivity of IkaD, indicating that substrate re-orientation by mutating residues distal to the oxidation site could serve as an important method in future engineering of P450 enzymes.

PubMed: 37917570
DOI: 10.1002/anie.202310728

Experimental method

X-RAY DIFFRACTION (2 Å)