|
|
| Line 1: |
Line 1: |
| | | | |
| | ==Crystal structure of sterol 14-alpha demethylase (CYP51) from Candida albicans in complex with the tetrazole-based antifungal drug candidate VT1161 (VT1)== | | ==Crystal structure of sterol 14-alpha demethylase (CYP51) from Candida albicans in complex with the tetrazole-based antifungal drug candidate VT1161 (VT1)== |
| - | <StructureSection load='5tz1' size='340' side='right' caption='[[5tz1]], [[Resolution|resolution]] 2.00Å' scene=''> | + | <StructureSection load='5tz1' size='340' side='right'caption='[[5tz1]], [[Resolution|resolution]] 2.00Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5tz1]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Atcc_11006_[[candida_stellatoidea]] Atcc 11006 [[candida stellatoidea]]]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5TZ1 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5TZ1 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5tz1]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Candida_albicans Candida albicans]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5TZ1 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5TZ1 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=VT1:(R)-2-(2,4-DIFLUOROPHENYL)-1,1-DIFLUORO-3-(1H-TETRAZOL-1-YL)-1-(5-(4-(2,2,2-TRIFLUOROETHOXY)PHENYL)PYRIDIN-2-YL)PROPAN-2-OL'>VT1</scene></td></tr> | + | </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=VT1:(R)-2-(2,4-DIFLUOROPHENYL)-1,1-DIFLUORO-3-(1H-TETRAZOL-1-YL)-1-(5-(4-(2,2,2-TRIFLUOROETHOXY)PHENYL)PYRIDIN-2-YL)PROPAN-2-OL'>VT1</scene></td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5fsa|5fsa]]</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=5tz1 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5tz1 OCA], [https://pdbe.org/5tz1 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5tz1 RCSB], [https://www.ebi.ac.uk/pdbsum/5tz1 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5tz1 ProSAT]</span></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">CYP51, ERG11 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=5476 ATCC 11006 [[Candida stellatoidea]]])</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'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5tz1 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5tz1 OCA], [http://pdbe.org/5tz1 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5tz1 RCSB], [http://www.ebi.ac.uk/pdbsum/5tz1 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5tz1 ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | + | == Function == |
| | + | [https://www.uniprot.org/uniprot/CP51_CANAL CP51_CANAL] Catalyzes C14-demethylation of lanosterol which is critical for ergosterol biosynthesis. 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 == |
| Line 23: |
Line 22: |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Sterol 14-demethylase]] | + | [[Category: Candida albicans]] |
| - | [[Category: Hargrove, T]] | + | [[Category: Large Structures]] |
| - | [[Category: Lepesheva, G]] | + | [[Category: Hargrove T]] |
| - | [[Category: Wawrzak, Z]] | + | [[Category: Lepesheva G]] |
| - | [[Category: Cyp51]] | + | [[Category: Wawrzak Z]] |
| - | [[Category: Cytochrome p450]]
| + | |
| - | [[Category: Cytochrome p450 fold]]
| + | |
| - | [[Category: Endoplasmic reticulum membrane]]
| + | |
| - | [[Category: Eukaryotic membrane]]
| + | |
| - | [[Category: Heme]]
| + | |
| - | [[Category: Monooxygenase]]
| + | |
| - | [[Category: Oxidoreductase]]
| + | |
| - | [[Category: Oxidoreductase-oxidoreductase inhibitor complex]]
| + | |
| - | [[Category: Sterol biosynthesis]]
| + | |
| Structural highlights
Function
CP51_CANAL Catalyzes C14-demethylation of lanosterol which is critical for ergosterol biosynthesis. It transforms lanosterol into 4,4'-dimethyl cholesta-8,14,24-triene-3-beta-ol.
Publication Abstract from PubMed
With some advances in modern medicine (such as cancer chemotherapy, broad exposure to antibiotics, and immunosuppression) the incidence of opportunistic fungal pathogens such as Candida albicans has increased. Cases of drug resistance among these pathogens have become more frequent, requiring the development of new drugs and a better understanding of the targeted enzymes. Sterol 14alpha-demethylase (CYP51) is a cytochrome P450 enzyme required for biosynthesis of sterols in eukaryotic cells and the major target of clinical drugs for managing fungal pathogens, but some of the CYP51 key features important for rational drug design have remained obscure. We report the catalytic properties, ligand-binding profiles, and inhibition of enzymatic activity of C. albicans CYP51 by clinical antifungal drugs that are used systemically (fluconazole, voriconazole, ketoconazole, itraconazole, and posaconazole) and topically (miconazole and clotrimazole) and by a tetrazole-based drug candidate, VT-1161 (oteseconazole; (R)-2- (2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1- yl)-1-(5-(4-(2,2,2-trifluoroethoxy) phenyl)pyridin-2- yl)propan-2-ol). Among the compounds tested, the first-line drug fluconazole was the weakest inhibitor, while posaconazole and VT-1161 were the strongest CYP51 inhibitors. We determined the X-ray structures of C. albicans CYP51 complexes with posaconazole and VT-1161, providing a molecular mechanism for the potencies of these drugs, including the activity of VT-1161 against C. krusei and C. glabrata, pathogens that are intrinsically resistant to fluconazole. Our comparative structural analysis outlines phylum-specific CYP51 features that could direct future rational development of more efficient broad-spectrum antifungals.
Structural Analyses of Candida albicans Sterol 14alpha-Demethylase Complexed with Azole Drugs Address the Molecular Basis of Azole-mediated Inhibition of Fungal Sterol Biosynthesis.,Hargrove TY, Friggeri L, Wawrzak Z, Qi A, Hoekstra WJ, Schotzinger RJ, York JD, Guengerich FP, Lepesheva GI J Biol Chem. 2017 Mar 3. pii: jbc.M117.778308. doi: 10.1074/jbc.M117.778308. PMID:28258218[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Hargrove TY, Friggeri L, Wawrzak Z, Qi A, Hoekstra WJ, Schotzinger RJ, York JD, Guengerich FP, Lepesheva GI. Structural Analyses of Candida albicans Sterol 14alpha-Demethylase Complexed with Azole Drugs Address the Molecular Basis of Azole-mediated Inhibition of Fungal Sterol Biosynthesis. J Biol Chem. 2017 Mar 3. pii: jbc.M117.778308. doi: 10.1074/jbc.M117.778308. PMID:28258218 doi:http://dx.doi.org/10.1074/jbc.M117.778308
|
