1jip
From Proteopedia
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| - | [[Image:1jip.jpg|left|200px]] | + | [[Image:1jip.jpg|left|200px]] |
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| - | '''P450eryF(A245S)/ketoconazole''' | + | {{Structure |
| + | |PDB= 1jip |SIZE=350|CAPTION= <scene name='initialview01'>1jip</scene>, resolution 2.Å | ||
| + | |SITE= | ||
| + | |LIGAND= <scene name='pdbligand=HEM:PROTOPORPHYRIN+IX+CONTAINING+FE'>HEM</scene> and <scene name='pdbligand=KTN:CIS-1-ACETYL-4-(4-((2-(2,4-DICHLOROPHENYL)-2-(1H-IMIDAZOL-1-YLMETHYL)-1,3-DIOXOLAN-4-YL)METHOXY)PHENYL)PIPERAZINE'>KTN</scene> | ||
| + | |ACTIVITY= | ||
| + | |GENE= | ||
| + | }} | ||
| + | |||
| + | '''P450eryF(A245S)/ketoconazole''' | ||
| + | |||
==Overview== | ==Overview== | ||
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==About this Structure== | ==About this Structure== | ||
| - | 1JIP is a [ | + | 1JIP is a [[Single protein]] structure of sequence from [http://en.wikipedia.org/wiki/Saccharopolyspora_erythraea Saccharopolyspora erythraea]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1JIP OCA]. |
==Reference== | ==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:[http:// | + | 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:[http://www.ncbi.nlm.nih.gov/pubmed/11469860 11469860] |
[[Category: Saccharopolyspora erythraea]] | [[Category: Saccharopolyspora erythraea]] | ||
[[Category: Single protein]] | [[Category: Single protein]] | ||
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[[Category: p450eryf(a245s)]] | [[Category: p450eryf(a245s)]] | ||
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Mar 20 12:04:03 2008'' |
Revision as of 10:04, 20 March 2008
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| , resolution 2.Å | |||||||
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| Ligands: | and | ||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||
P450eryF(A245S)/ketoconazole
Overview
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.
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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