1JIN

P450eryF/ketoconazole

Summary for 1JIN

• Entry DOI: 10.2210/pdb1jin/pdb
• Descriptor: CYTOCHROME P450 107A1, PROTOPORPHYRIN IX CONTAINING FE, CIS-1-ACETYL-4-(4-((2-(2,4-DICHLOROPHENYL)-2-(1H-IMIDAZOL-1-YLMETHYL)-1,3-DIOXOLAN-4-YL)METHOXY)PHENYL)PIPERAZINE, ... (4 entities in total)
• Functional Keywords: cytochrome p450, p450, p450eryf, ketoconazole, azole drug, hydrolase
• Biological source: Saccharopolyspora erythraea
• Cellular location: Cytoplasm (By similarity): Q00441
• Total number of polymer chains: 1
• Total formula weight: 45663.07

Authors

Cupp-Vickery, J.R.,Garcia, C.,Hofacre, A.,McGee-Estrada, K. (deposition date: 2001-07-02, release date: 2001-10-17, Last modification date: 2024-04-03)

Primary citation

Cupp-Vickery, J.R.,Garcia, C.,Hofacre, A.,McGee-Estrada, K.
Ketoconazole-induced conformational changes in the active site of cytochrome P450eryF.
J.Mol.Biol., 311:101-110, 2001

PubMed Abstract: The azole-based P450 inhibitor ketoconazole is used to treat fungal infections and functions by blocking ergosterol biosynthesis in yeast. Ketoconazole binds to mammalian P450 enzymes and this can result in drug-drug interactions and lead to liver damage. To identify protein-drug interactions that contribute to binding specificity and affinity, we determined the crystal structure of ketoconazole complexed with P450eryF. In the P450eryF/ketoconazole structure, the azole moiety and nearby rings of ketoconzole are positioned in the active site similar to the substrate, 6-deoxyerythronolide B, with the azole nitrogen atom coordinated to the heme iron atom. The remainder of the ketoconazole molecule extends into the active-site pocket, which is occupied by water in the substrate complex. Binding of ketoconazole led to unexpected conformational changes in the I-helix. The I-helix cleft near the active site has collapsed with a helical pitch of 5.4 A compared to 6.6 A in the substrate complex. P450eryF/ketoconazole crystals soaked in 6-deoxyerythronolide B to exchange ligands exhibit a structure identical with that of the original P450eryF/substrate complex, with the I-helix cleft restored to a pitch of 6.6 A. These findings indicate that the I-helix region of P450eryF is flexible and can adopt multiple conformations. An improved understanding of the flexibility of the active-site region of cytochrome P450 enzymes is important to gain insight into determinants of ligand binding/specificity as well as to evaluate models for catalytic mechanism based on static crystal structures.

PubMed: 11469860
DOI: 10.1006/jmbi.2001.4803

Experimental method

X-RAY DIFFRACTION (2.3 Å)