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| | <StructureSection load='3zg3' size='340' side='right'caption='[[3zg3]], [[Resolution|resolution]] 2.90Å' scene=''> | | <StructureSection load='3zg3' size='340' side='right'caption='[[3zg3]], [[Resolution|resolution]] 2.90Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[3zg3]] 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=3ZG3 OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=3ZG3 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[3zg3]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Trycr Trycr]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3ZG3 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3ZG3 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=UDD:N-[4-(TRIFLUOROMETHYL)PHENYL]-N-[1-[5-(TRIFLUOROMETHYL)PYRIDIN-2-YL]PIPERIDIN-4-YL]PYRIDIN-3-AMINE'>UDD</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=UDD:N-[4-(TRIFLUOROMETHYL)PHENYL]-N-[1-[5-(TRIFLUOROMETHYL)PYRIDIN-2-YL]PIPERIDIN-4-YL]PYRIDIN-3-AMINE'>UDD</scene></td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3zg2|3zg2]]</td></tr> | + | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[3zg2|3zg2]]</div></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='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Sterol_14-demethylase Sterol 14-demethylase], with EC number [https://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://proteopedia.org/fgij/fg.htm?mol=3zg3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3zg3 OCA], [http://pdbe.org/3zg3 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3zg3 RCSB], [http://www.ebi.ac.uk/pdbsum/3zg3 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=3zg3 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=3zg3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3zg3 OCA], [https://pdbe.org/3zg3 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3zg3 RCSB], [https://www.ebi.ac.uk/pdbsum/3zg3 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3zg3 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] |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
| 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]
Publication Abstract from PubMed
Chagas disease, caused by the eukaryotic (protozoan) parasite Trypanosoma cruzi, is an alarming emerging global health problem with no clinical drugs available to treat the chronic stage. Azole inhibitors of sterol 14alpha-demethylase (CYP51) were proven effective against Chagas, and antifungal drugs posaconazole and ravuconazole entered clinical trials in Spain, Bolivia and Argentina. Here we present the X-ray structures of T.cruzi CYP51 in complexes with two alternative drug candidates, pyridine derivatives (S)-(4-chlorophenyl)-1-(4-(4-(trifluoromethyl)phenyl)- piperazin-1-yl)-2-(pyridin-3-yl)ethanone (UDO) and N-[4-(trifluoromethyl)phenyl]-N-[1-[5-(trifluoromethyl)-2-pyridyl]-4-piperi-dyl]p yridin-3-amine (UDD). These compounds have been developed by Drugs for Neglected Diseases initiative (DNDi) and are highly promising antichagasic agents, both in cellular and in vivo experiments. Binding parameters and inhibitory effects on sterol 14alpha-demethylase activity in reconstituted enzyme reactions confirm UDO and UDD as potent and selective T. cruzi CYP51 inhibitors. Comparative analysis of the pyridine- and azole-bound CYP51 structures uncovers the features which make UDO and UDD T. cruzi CYP51 specific. The structures suggest that while precise fit between the shape of the inhibitor molecules and T. cruzi CYP51 active site topology underlies their high inhibitory potency, a longer coordination bond between the catalytic heme iron and the pyridine nitrogen implies weaker influence of pyridines on the iron reduction potential, which may be the basis for the observed selectivity of these compounds towards the target enzyme versus other CYPs, including human drug-metabolizing P450s. The findings might pave the way for the development of novel CYP51-targeted drugs with optimized metabolic properties that are highly needed for treatment of human infections caused by eukaryotic microbial pathogens.
Complexes of Trypanosoma cruzi sterol 14alpha-demethylase (CYP51) with two pyridine-based drug candidates for Chagas disease: Structural basis for pathogen-selectivity.,Hargrove TY, Wawrzak Z, Alexander PW, Chaplin JH, Keenan M, Charman SA, Perez CJ, Waterman MR, Chatelain E, Lepesheva GI J Biol Chem. 2013 Sep 18. PMID:24047900[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
- ↑ Hargrove TY, Wawrzak Z, Alexander PW, Chaplin JH, Keenan M, Charman SA, Perez CJ, Waterman MR, Chatelain E, Lepesheva GI. Complexes of Trypanosoma cruzi sterol 14alpha-demethylase (CYP51) with two pyridine-based drug candidates for Chagas disease: Structural basis for pathogen-selectivity. J Biol Chem. 2013 Sep 18. PMID:24047900 doi:10.1074/jbc.M113.497990
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