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| | {{STRUCTURE_1jip| PDB=1jip | SCENE= }} | | {{STRUCTURE_1jip| PDB=1jip | SCENE= }} |
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| - | '''P450eryF(A245S)/ketoconazole'''
| + | ===P450eryF(A245S)/ketoconazole=== |
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| - | ==Overview==
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| - | 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. | + | The line below this paragraph, {{ABSTRACT_PUBMED_11469860}}, adds the Publication Abstract to the page |
| | + | (as it appears on PubMed at http://www.pubmed.gov), where 11469860 is the PubMed ID number. |
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| | + | {{ABSTRACT_PUBMED_11469860}} |
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| | ==About this Structure== | | ==About this Structure== |
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| | [[Category: Ketoconazole]] | | [[Category: Ketoconazole]] |
| | [[Category: P450eryf]] | | [[Category: P450eryf]] |
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Fri May 2 21:16:17 2008'' | + | |
| | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Tue Jul 1 20:18:23 2008'' |
Revision as of 17:18, 1 July 2008
Template:STRUCTURE 1jip
P450eryF(A245S)/ketoconazole
Template:ABSTRACT PUBMED 11469860
About this Structure
1JIP is a Single protein structure of sequence from Saccharopolyspora erythraea. Full crystallographic information is available from OCA.
Reference
Ketoconazole-induced conformational changes in the active site of cytochrome P450eryF., Cupp-Vickery JR, Garcia C, Hofacre A, McGee-Estrada K, J Mol Biol. 2001 Aug 3;311(1):101-10. PMID:11469860
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