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1jip

From Proteopedia

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[[Image:1jip.jpg|left|200px]]<br /><applet load="1jip" size="350" color="white" frame="true" align="right" spinBox="true"
 
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caption="1jip, resolution 2.&Aring;" />
 
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'''P450eryF(A245S)/ketoconazole'''<br />
 
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==Overview==
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==P450eryF(A245S)/ketoconazole==
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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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<StructureSection load='1jip' size='340' side='right'caption='[[1jip]], [[Resolution|resolution]] 2.00&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[1jip]] is a 1 chain structure with sequence from [https://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]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1JIP FirstGlance]. <br>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2&#8491;</td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=HEM:PROTOPORPHYRIN+IX+CONTAINING+FE'>HEM</scene>, <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></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=1jip FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1jip OCA], [https://pdbe.org/1jip PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1jip RCSB], [https://www.ebi.ac.uk/pdbsum/1jip PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1jip ProSAT]</span></td></tr>
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</table>
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== Function ==
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[https://www.uniprot.org/uniprot/CPXJ_SACEN CPXJ_SACEN] Catalyzes the NADPH-dependent conversion of 6-deoxyerythronolide B (6-DEB) to erythronolide B (EB) by the insertion of an oxygen at the 6S position of 6-DEB. Requires the participation of a ferredoxin and a ferredoxin reductase for the transfer of electrons from NADPH to the monooxygenase.<ref>PMID:1732208</ref> <ref>PMID:2011746</ref>
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== Evolutionary Conservation ==
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[[Image:Consurf_key_small.gif|200px|right]]
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Check<jmol>
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<jmolCheckbox>
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<scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/ji/1jip_consurf.spt"</scriptWhenChecked>
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<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
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<text>to colour the structure by Evolutionary Conservation</text>
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</jmolCheckbox>
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</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=1jip ConSurf].
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<div style="clear:both"></div>
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==About this Structure==
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==See Also==
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1JIP is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Saccharopolyspora_erythraea Saccharopolyspora erythraea] with <scene name='pdbligand=HEM:'>HEM</scene> and <scene name='pdbligand=KTN:'>KTN</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1JIP OCA].
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*[[Cytochrome P450 3D structures|Cytochrome P450 3D structures]]
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== References ==
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==Reference==
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<references/>
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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://ispc.weizmann.ac.il//pmbin/getpm?pmid=11469860 11469860]
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__TOC__
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</StructureSection>
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[[Category: Large Structures]]
[[Category: Saccharopolyspora erythraea]]
[[Category: Saccharopolyspora erythraea]]
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[[Category: Single protein]]
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[[Category: Cupp-Vickery JR]]
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[[Category: Cupp-Vickery, J R.]]
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[[Category: Garcia C]]
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[[Category: Garcia, C.]]
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[[Category: Hofacre A]]
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[[Category: Hofacre, A.]]
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[[Category: McGee-Estrada K]]
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[[Category: McGee-Estrada, K.]]
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[[Category: HEM]]
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[[Category: KTN]]
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[[Category: azole drug]]
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[[Category: cytochrome p450]]
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[[Category: ketoconazole]]
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[[Category: p450eryf]]
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[[Category: p450eryf(a245s)]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 13:23:05 2008''
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Current revision

P450eryF(A245S)/ketoconazole

PDB ID 1jip

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