4g3j

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==Sterol 14-alpha demethylase (CYP51) from Trypanosoma brucei in complex with the VNI derivative (R)-N-(1-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-yl)ethyl)-4-(5-phenyl-1,3,4-oxadiazol-2-yl)benzamide [R-VNI-triazole (VNT)]==
==Sterol 14-alpha demethylase (CYP51) from Trypanosoma brucei in complex with the VNI derivative (R)-N-(1-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-yl)ethyl)-4-(5-phenyl-1,3,4-oxadiazol-2-yl)benzamide [R-VNI-triazole (VNT)]==
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<StructureSection load='4g3j' size='340' side='right' caption='[[4g3j]], [[Resolution|resolution]] 1.83&Aring;' scene=''>
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<StructureSection load='4g3j' size='340' side='right'caption='[[4g3j]], [[Resolution|resolution]] 1.83&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>[[4g3j]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/Trypanosoma_(trypanozoon)_brucei Trypanosoma (trypanozoon) brucei]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4G3J OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4G3J FirstGlance]. <br>
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<table><tr><td colspan='2'>[[4g3j]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Trypanosoma_brucei Trypanosoma brucei]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4G3J OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4G3J FirstGlance]. <br>
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=HEM:PROTOPORPHYRIN+IX+CONTAINING+FE'>HEM</scene>, <scene name='pdbligand=VNT:N-[(1R)-1-(2,4-DICHLOROPHENYL)-2-(1H-1,2,4-TRIAZOL-1-YL)ETHYL]-4-(5-PHENYL-1,3,4-OXADIAZOL-2-YL)BENZAMIDE'>VNT</scene></td></tr>
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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]] 1.83&#8491;</td></tr>
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<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3gw9|3gw9]], [[4g7g|4g7g]]</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=VNT:N-[(1R)-1-(2,4-DICHLOROPHENYL)-2-(1H-1,2,4-TRIAZOL-1-YL)ETHYL]-4-(5-PHENYL-1,3,4-OXADIAZOL-2-YL)BENZAMIDE'>VNT</scene></td></tr>
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<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">CYP51, Tb11.02.4080 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=5691 Trypanosoma (Trypanozoon) brucei])</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=4g3j FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4g3j OCA], [https://pdbe.org/4g3j PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4g3j RCSB], [https://www.ebi.ac.uk/pdbsum/4g3j PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4g3j ProSAT]</span></td></tr>
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<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Sterol_14-demethylase Sterol 14-demethylase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.14.13.70 1.14.13.70] </span></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4g3j FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4g3j OCA], [http://pdbe.org/4g3j PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4g3j RCSB], [http://www.ebi.ac.uk/pdbsum/4g3j PDBsum]</span></td></tr>
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</table>
</table>
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<div style="background-color:#fffaf0;">
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== Function ==
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== Publication Abstract from PubMed ==
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[https://www.uniprot.org/uniprot/Q385E8_TRYB2 Q385E8_TRYB2]
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Sterol 14alpha-demethylases (CYP51) are the enzymes essential for sterol biosynthesis. They serve as clinical targets for antifungal azoles and are considered as targets for treatment of human Trypanosomatidae infections. Recently, we have shown that VNI, a potent and selective inhibitor of trypanosomal CYP51 that we identified and structurally characterized in complex with the enzyme, can cure the acute and chronic forms of Chagas disease. The purpose of this work was to apply the CYP51 structure/function for further development of the VNI scaffold. As anticipated, VFV, the derivative designed to fill the deepest portion of the CYP51 substrate binding cavity, reveals a broader antiprotozoan spectrum of action. It has stronger antiparasitic activity in cellular experiments, cures the experimental Chagas disease with 100% efficacy, and suppresses visceral leishmaniasis by 89% (vs. 60% for VNI). Oral bioavailability, low off-target activity, favorable pharmacokinetics and tissue distribution characterize VFV as a promising new drug candidate.
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VFV as a new effective CYP51 structure-derived drug candidate for Chagas disease and visceral leishmaniasis.,Lepesheva GI, Hargrove TY, Rachakonda G, Wawrzak Z, Pomel S, Cojean S, Nde PN, Nes WD, Locuson CW, Calcutt MW, Waterman MR, Daniels JS, Loiseau PM, Villalta F J Infect Dis. 2015 Apr 15. pii: jiv228. PMID:25883390<ref>PMID:25883390</ref>
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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==See Also==
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</div>
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*[[Cytochrome P450 3D structures|Cytochrome P450 3D structures]]
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<div class="pdbe-citations 4g3j" style="background-color:#fffaf0;"></div>
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== References ==
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<references/>
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__TOC__
__TOC__
</StructureSection>
</StructureSection>
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[[Category: Sterol 14-demethylase]]
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[[Category: Large Structures]]
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[[Category: Hargrove, T Y]]
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[[Category: Trypanosoma brucei]]
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[[Category: Lepesheva, G I]]
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[[Category: Hargrove TY]]
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[[Category: Waterman, M R]]
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[[Category: Lepesheva GI]]
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[[Category: Wawrzak, Z]]
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[[Category: Waterman MR]]
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[[Category: Cytochrome p450 fold]]
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[[Category: Wawrzak Z]]
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[[Category: Cytochrome p450 reductase]]
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[[Category: Endoplasmic reticulum membrane]]
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[[Category: Eukaryotic membrane biogenesis]]
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[[Category: Heme]]
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[[Category: Monooxygenase]]
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[[Category: Oxidoreductase-oxidoreductase inhibitor complex]]
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[[Category: Sterol biosynthesis]]
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Current revision

Sterol 14-alpha demethylase (CYP51) from Trypanosoma brucei in complex with the VNI derivative (R)-N-(1-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-yl)ethyl)-4-(5-phenyl-1,3,4-oxadiazol-2-yl)benzamide [R-VNI-triazole (VNT)]

PDB ID 4g3j

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Proteopedia Page Contributors and Editors (what is this?)

OCA

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