4UBS
The crystal structure of cytochrome P450 105D7 from Streptomyces avermitilis in complex with Diclofenac
Summary for 4UBS
| Entry DOI | 10.2210/pdb4ubs/pdb |
| Descriptor | Pentalenic acid synthase, PROTOPORPHYRIN IX CONTAINING FE, 2-[2,6-DICHLOROPHENYL)AMINO]BENZENEACETIC ACID, ... (7 entities in total) |
| Functional Keywords | cytochrome p450, diclofenac, hydroxylation, oxidoreductase |
| Biological source | Streptomyces avermitilis MA-4680 = NBRC 14893 |
| Total number of polymer chains | 1 |
| Total formula weight | 46814.57 |
| Authors | Xu, L.H.,Ikeda, H.,Arakawa, T.,Wakagi, T.,Shoun, H.,Fushinobu, S. (deposition date: 2014-08-13, release date: 2014-11-05, Last modification date: 2024-03-20) |
| Primary citation | Xu, L.H.,Ikeda, H.,Liu, L.,Arakawa, T.,Wakagi, T.,Shoun, H.,Fushinobu, S. Structural basis for the 4'-hydroxylation of diclofenac by a microbial cytochrome P450 monooxygenase. Appl.Microbiol.Biotechnol., 99:3081-3091, 2015 Cited by PubMed Abstract: Diclofenac is a nonsteroidal anti-inflammatory drug. It undergoes hydroxylation by mammalian cytochrome P450 enzymes at 4'- and/or 5'-positions. A bacterial P450 enzyme, CYP105D7 from Streptomyces avermitilis, has been shown to catalyze hydroxylation of 1-deoxypentalenic acid and an isoflavone daidzein. Here, we demonstrated that CYP105D7 also catalyzes hydroxylation of diclofenac at the C4'-position. A spectroscopic analysis showed that CYP105D7 binds diclofenac in a slightly cooperative manner with an affinity of 65 μM and a Hill coefficient of 1.16. The crystal structure of CYP105D7 in complex with diclofenac was determined at 2.2 Å resolution. The distal pocket of CYP105D7 contains two diclofenac molecules, illustrating drug recognition with a double-ligand-binding mode. The C3' and C4' atoms of the dichlorophenyl ring of one diclofenac molecule are positioned near the heme iron, suggesting that it is positioned appropriately for aromatic hydroxylation to yield the 4'-hydroxylated product. However, recognition of diclofenac by CYP105D7 was completely different from that of rabbit CYP2C5, which binds one diclofenac molecule with a cluster of water molecules. The distal pocket of CYP105D7 contains four arginine residues, forming a wall of the substrate-binding pocket, and the arginine residues are conserved in bacterial P450s in the CYP105 family. PubMed: 25341403DOI: 10.1007/s00253-014-6148-y PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.2 Å) |
Structure validation
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