|
|
| (One intermediate revision not shown.) |
| Line 1: |
Line 1: |
| | | | |
| | ==Crystal structure of sterol 14-alpha demethylase (CYP51) from Trypanosoma cruzi in complex with a potential antichagasic drug, posaconazole== | | ==Crystal structure of sterol 14-alpha demethylase (CYP51) from Trypanosoma cruzi in complex with a potential antichagasic drug, posaconazole== |
| - | <StructureSection load='3k1o' size='340' side='right' caption='[[3k1o]], [[Resolution|resolution]] 2.89Å' scene=''> | + | <StructureSection load='3k1o' size='340' side='right'caption='[[3k1o]], [[Resolution|resolution]] 2.89Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[3k1o]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Trycr Trycr]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3K1O OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3K1O FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[3k1o]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Trypanosoma_cruzi Trypanosoma cruzi]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3K1O OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3K1O 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=POZ:2,5-anhydro-1,3,4-trideoxy-2-(2,4-difluorophenyl)-6-O-{4-[4-(4-{1-[(1S,2S)-1-ethyl-2-hydroxypropyl]-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl}phenyl)piperazin-1-yl]phenyl}-1-(1H-1,2,4-triazol-1-yl)-D-erythro-hexitol'>POZ</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]] 2.89Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3g1q|3g1q]], [[3i3k|3i3k]]</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=POZ:2,5-anhydro-1,3,4-trideoxy-2-(2,4-difluorophenyl)-6-O-{4-[4-(4-{1-[(1S,2S)-1-ethyl-2-hydroxypropyl]-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl}phenyl)piperazin-1-yl]phenyl}-1-(1H-1,2,4-triazol-1-yl)-D-erythro-hexitol'>POZ</scene></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">CYP51 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=5693 TRYCR])</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=3k1o FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3k1o OCA], [https://pdbe.org/3k1o PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3k1o RCSB], [https://www.ebi.ac.uk/pdbsum/3k1o PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3k1o ProSAT]</span></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=3k1o FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3k1o OCA], [http://pdbe.org/3k1o PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3k1o RCSB], [http://www.ebi.ac.uk/pdbsum/3k1o PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=3k1o ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/CP51_TRYCC CP51_TRYCC]] 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 (By similarity). Favors C4 dimethylated substrates, the substrate preference order is 24-methylenedihydrolanosterol > 24,25-dihydrolanosterol > lanosterol > obtusifoliol > norlanosterol.<ref>PMID:16321980</ref> [UniProtKB:P0A512] | + | [https://www.uniprot.org/uniprot/CP51_TRYCC CP51_TRYCC] 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 (By similarity). Favors C4 dimethylated substrates, the substrate preference order is 24-methylenedihydrolanosterol > 24,25-dihydrolanosterol > lanosterol > obtusifoliol > norlanosterol.<ref>PMID:16321980</ref> [UniProtKB:P0A512] |
| | == Evolutionary Conservation == | | == Evolutionary Conservation == |
| | [[Image:Consurf_key_small.gif|200px|right]] | | [[Image:Consurf_key_small.gif|200px|right]] |
| Line 35: |
Line 33: |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Sterol 14-demethylase]] | + | [[Category: Large Structures]] |
| - | [[Category: Trycr]] | + | [[Category: Trypanosoma cruzi]] |
| - | [[Category: Anderson, S]] | + | [[Category: Anderson S]] |
| - | [[Category: Hargrove, T Y]] | + | [[Category: Hargrove TY]] |
| - | [[Category: Lepesheva, G I]] | + | [[Category: Lepesheva GI]] |
| - | [[Category: Waterman, M R]] | + | [[Category: Waterman MR]] |
| - | [[Category: Wawrzak, Z]] | + | [[Category: Wawrzak Z]] |
| - | [[Category: Cyp51]]
| + | |
| - | [[Category: Cytochrome p450]]
| + | |
| - | [[Category: Eburicol 14a-demethylase]]
| + | |
| - | [[Category: Endoplasmic reticulum]]
| + | |
| - | [[Category: Heme]]
| + | |
| - | [[Category: Heme-thiolate protein]]
| + | |
| - | [[Category: Iron]]
| + | |
| - | [[Category: Lipid]]
| + | |
| - | [[Category: Membrane]]
| + | |
| - | [[Category: Monooxygenase]]
| + | |
| - | [[Category: Oxidoreductase]]
| + | |
| - | [[Category: Sterol 14-alpha demethylase]]
| + | |
| - | [[Category: Sterol biosynthesis]]
| + | |
| - | [[Category: Transmembrane protein]]
| + | |
| Structural highlights
Function
CP51_TRYCC 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 (By similarity). Favors C4 dimethylated substrates, the substrate preference order is 24-methylenedihydrolanosterol > 24,25-dihydrolanosterol > lanosterol > obtusifoliol > norlanosterol.[1] [UniProtKB:P0A512]
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
Trypanosoma cruzi causes Chagas disease (American trypanosomiasis), which threatens the lives of millions of people and remains incurable in its chronic stage. The antifungal drug posaconazole that blocks sterol biosynthesis in the parasite is the only compound entering clinical trials for the chronic form of this infection. Crystal structures of the drug target enzyme, Trypanosoma cruzi sterol 14alpha-demethylase (CYP51), complexed with posaconazole, another antifungal agent fluconazole and an experimental inhibitor, (R)-4'-chloro-N-(1-(2,4-dichlorophenyl)-2-(1H-imid-azol-1-yl)ethyl)bipheny l-4-carboxamide (VNF), allow prediction of important chemical features that enhance the drug potencies. Combined with comparative analysis of inhibitor binding parameters, influence on the catalytic activity of the trypanosomal enzyme and its human counterpart, and their cellular effects at different stages of the Trypanosoma cruzi life cycle, the structural data provide a molecular background to CYP51 inhibition and azole resistance and enlighten the path for directed design of new, more potent and selective drugs to develop an efficient treatment for Chagas disease.
Structural insights into inhibition of sterol 14alpha-demethylase in the human pathogen Trypanosoma cruzi.,Lepesheva GI, Hargrove TY, Anderson S, Kleshchenko Y, Furtak V, Wawrzak Z, Villalta F, Waterman MR J Biol Chem. 2010 Aug 13;285(33):25582-90. Epub 2010 Jun 8. PMID:20530488[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Lepesheva GI, Zaitseva NG, Nes WD, Zhou W, Arase M, Liu J, Hill GC, Waterman MR. CYP51 from Trypanosoma cruzi: a phyla-specific residue in the B' helix defines substrate preferences of sterol 14alpha-demethylase. J Biol Chem. 2006 Feb 10;281(6):3577-85. Epub 2005 Nov 30. PMID:16321980 doi:M510317200
- ↑ Lepesheva GI, Hargrove TY, Anderson S, Kleshchenko Y, Furtak V, Wawrzak Z, Villalta F, Waterman MR. Structural insights into inhibition of sterol 14alpha-demethylase in the human pathogen Trypanosoma cruzi. J Biol Chem. 2010 Aug 13;285(33):25582-90. Epub 2010 Jun 8. PMID:20530488 doi:10.1074/jbc.M110.133215
|
