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1jip

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{{STRUCTURE_1jip| PDB=1jip | SCENE= }}
{{STRUCTURE_1jip| PDB=1jip | SCENE= }}
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'''P450eryF(A245S)/ketoconazole'''
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===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.
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{{ABSTRACT_PUBMED_11469860}}
==About this Structure==
==About this Structure==
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[[Category: Ketoconazole]]
[[Category: Ketoconazole]]
[[Category: P450eryf]]
[[Category: P450eryf]]
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Revision as of 17:18, 1 July 2008

Image:1jip.png

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

Page seeded by OCA on Tue Jul 1 20:18:23 2008

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