4g3j
From Proteopedia
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== Structural highlights == | == Structural highlights == | ||
<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> | <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> | ||
| - | </td></tr><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> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.83Å</td></tr> |
| + | <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> | ||
<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> | <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> | ||
</table> | </table> | ||
== Function == | == Function == | ||
[https://www.uniprot.org/uniprot/Q385E8_TRYB2 Q385E8_TRYB2] | [https://www.uniprot.org/uniprot/Q385E8_TRYB2 Q385E8_TRYB2] | ||
| - | <div style="background-color:#fffaf0;"> | ||
| - | == Publication Abstract from PubMed == | ||
| - | 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. | ||
| - | + | ==See Also== | |
| - | + | *[[Cytochrome P450 3D structures|Cytochrome P450 3D structures]] | |
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__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
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)]
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