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| | ==HUMAN STEROL 14-ALPHA DEMETHYLASE (CYP51) IN COMPLEX WITH VFV IN C121 SPACE GROUP== | | ==HUMAN STEROL 14-ALPHA DEMETHYLASE (CYP51) IN COMPLEX WITH VFV IN C121 SPACE GROUP== |
| - | <StructureSection load='4uhi' size='340' side='right' caption='[[4uhi]], [[Resolution|resolution]] 2.04Å' scene=''> | + | <StructureSection load='4uhi' size='340' side='right'caption='[[4uhi]], [[Resolution|resolution]] 2.04Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4uhi]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4UHI OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4UHI FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4uhi]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4UHI OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4UHI FirstGlance]. <br> |
| - | </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=VFV:N-[(1R)-1-(3,4-DIFLUOROBIPHENYL-4-YL)-2-(1H-IMIDAZOL-1-YL)ETHYL]-4-(5-PHENYL-1,3,4-OXADIAZOL-2-YL)BENZAMIDE'>VFV</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]] 2.04Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4uhl|4uhl]]</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=VFV:N-[(1R)-1-(3,4-DIFLUOROBIPHENYL-4-YL)-2-(1H-IMIDAZOL-1-YL)ETHYL]-4-(5-PHENYL-1,3,4-OXADIAZOL-2-YL)BENZAMIDE'>VFV</scene></td></tr> |
| - | <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>
| + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4uhi FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4uhi OCA], [https://pdbe.org/4uhi PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4uhi RCSB], [https://www.ebi.ac.uk/pdbsum/4uhi PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4uhi ProSAT]</span></td></tr> |
| - | <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=4uhi FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4uhi OCA], [http://pdbe.org/4uhi PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4uhi RCSB], [http://www.ebi.ac.uk/pdbsum/4uhi PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4uhi ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/CP51A_HUMAN CP51A_HUMAN]] Catalyzes C14-demethylation of lanosterol; it transforms lanosterol into 4,4'-dimethyl cholesta-8,14,24-triene-3-beta-ol. | + | [https://www.uniprot.org/uniprot/CP51A_HUMAN CP51A_HUMAN] Catalyzes C14-demethylation of lanosterol; it transforms lanosterol into 4,4'-dimethyl cholesta-8,14,24-triene-3-beta-ol. |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | </div> | | </div> |
| | <div class="pdbe-citations 4uhi" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 4uhi" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[Cytochrome P450 3D structures|Cytochrome P450 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Sterol 14-demethylase]] | + | [[Category: Large Structures]] |
| - | [[Category: Hargrove, T Y]] | + | [[Category: Hargrove TY]] |
| - | [[Category: Lepesheva, G I]] | + | [[Category: I Lepesheva G]] |
| - | [[Category: Wawrzak, Z]] | + | [[Category: Wawrzak Z]] |
| - | [[Category: Cytochrome p450 fold]]
| + | |
| - | [[Category: Endoplasmic reticulum]]
| + | |
| - | [[Category: Eukaryotic membrane]]
| + | |
| - | [[Category: Monooxygenase]]
| + | |
| - | [[Category: Oxidoreductase]]
| + | |
| - | [[Category: Sterol biosynthesis]]
| + | |
| Structural highlights
Function
CP51A_HUMAN Catalyzes C14-demethylation of lanosterol; it transforms lanosterol into 4,4'-dimethyl cholesta-8,14,24-triene-3-beta-ol.
Publication Abstract from PubMed
Rapidly multiplying cancer cells synthesize greater amounts of cholesterol to build their membranes. Cholesterol-lowering drugs (statins) are currently in clinical trials for anticancer chemotherapy. However, given at higher doses statins cause serious side effects by inhibiting the formation of other biologically important molecules derived from mevalonate. Sterol 14alpha-demethylase (CYP51), which acts 10 steps downstream, is potentially a more specific drug target because this portion of the pathway is fully committed to cholesterol production. However, screening a variety of commercial and experimental inhibitors of microbial CYP51 orthologs revealed that most of them (including all clinical antifungals) weakly inhibit human CYP51 activity, even if they display high apparent spectral binding affinity. Only one relatively potent compound, VFV ((R)-N-(1-(3,4'-difluorobiphenyl-4-yl)-2-(1H-imidazol-1-yl)ethyl)-4-(5-phenyl-1,3 ,4-oxadiazol-2-yl)benzamide), was identified. VFV has been further tested in cellular experiments and found to decrease proliferation of different cancer cell types. The crystal structures of human CYP51-VFV complexes (2.0 and 2.5 A) both display a 2:1 inhibitor/enzyme stoichiometry, provide molecular insights regarding a broader substrate profile, faster catalysis, and weaker susceptibility of human CYP51 to inhibition and outline directions for the development of more potent inhibitors.
Human sterol 14alpha-demethylase (CYP51) as a target for anticancer chemotherapy: Towards structure-aided drug design.,Hargrove TY, Friggeri L, Wawrzak Z, Sivakumaran S, Yazlovitskaya EM, Hiebert SW, Guengerich FP, Waterman MR, Lepesheva GI J Lipid Res. 2016 Jun 16. pii: jlr.M069229. PMID:27313059[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Hargrove TY, Friggeri L, Wawrzak Z, Sivakumaran S, Yazlovitskaya EM, Hiebert SW, Guengerich FP, Waterman MR, Lepesheva GI. Human sterol 14alpha-demethylase (CYP51) as a target for anticancer chemotherapy: Towards structure-aided drug design. J Lipid Res. 2016 Jun 16. pii: jlr.M069229. PMID:27313059 doi:http://dx.doi.org/10.1194/jlr.M069229
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