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| | <StructureSection load='4cka' size='340' side='right'caption='[[4cka]], [[Resolution|resolution]] 2.70Å' scene=''> | | <StructureSection load='4cka' size='340' side='right'caption='[[4cka]], [[Resolution|resolution]] 2.70Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4cka]] 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=4CKA OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4CKA FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4cka]] 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=4CKA OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4CKA 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=LFS:(1S)-1-(4-FLUOROPHENYL)-2-(1H-IMIDAZOL-1-YL)ETHYL+4-ISOPROPYLPHENYLCARBAMATE'>LFS</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=LFS:(1S)-1-(4-FLUOROPHENYL)-2-(1H-IMIDAZOL-1-YL)ETHYL+4-ISOPROPYLPHENYLCARBAMATE'>LFS</scene></td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4ck8|4ck8]], [[4ck9|4ck9]]</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=4cka FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4cka OCA], [https://pdbe.org/4cka PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4cka RCSB], [https://www.ebi.ac.uk/pdbsum/4cka PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4cka 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=4cka FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4cka OCA], [http://pdbe.org/4cka PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4cka RCSB], [http://www.ebi.ac.uk/pdbsum/4cka PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4cka 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 == |
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| | </StructureSection> | | </StructureSection> |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Sterol 14-demethylase]] | + | [[Category: Trypanosoma cruzi]] |
| - | [[Category: Trycr]]
| + | [[Category: Friggeri L]] |
| - | [[Category: Friggeri, L]] | + | [[Category: Lepesheva GI]] |
| - | [[Category: Lepesheva, G I]] | + | [[Category: Tortorella S]] |
| - | [[Category: Tortorella, S]] | + | [[Category: Wawrzak Z]] |
| - | [[Category: Wawrzak, Z]] | + | |
| - | [[Category: Cytochrome p450 fold]]
| + | |
| - | [[Category: Endoplasmic reticulum membrane]]
| + | |
| - | [[Category: Eukaryotic membrane]]
| + | |
| - | [[Category: Heme]]
| + | |
| - | [[Category: Monooxygenase]]
| + | |
| - | [[Category: Oxidoreductase]]
| + | |
| - | [[Category: Sterol biosynthesis]]
| + | |
| 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, which was once thought to be confined to endemic regions of Latin America, has now gone global, becoming a new worldwide challenge with no cure available. The disease is caused by the protozoan parasite Trypanosoma cruzi, which depends on the production of endogenous sterols, and therefore can be blocked by sterol 14alpha-demethylase (CYP51) inhibitors. Here we explore the spectral binding parameters, inhibitory effects on T. cruzi CYP51 activity, and antiparasitic potencies of a new set of beta-phenyl imidazoles. Comparative structural characterization of the T. cruzi CYP51 complexes with the three most potent inhibitors reveals two opposite binding modes of the compounds ((R)-6, EC50 = 1.2 nM, vs (S)-2/(S)-3, EC50 = 1.0/5.5 nM) and suggests the entrance into the CYP51 substrate access channel and the heme propionate-supporting ceiling of the binding cavity as two distinct areas of the protein that enhance molecular recognition and therefore could be used for the development of more effective antiparasitic drugs.
Structural Basis for Rational Design of Inhibitors Targeting Trypanosoma cruzi Sterol 14alpha-Demethylase: Two Regions of the Enzyme Molecule Potentiate Its Inhibition.,Friggeri L, Hargrove TY, Rachakonda G, Williams AD, Wawrzak Z, Di Santo R, De Vita D, Waterman MR, Tortorella S, Villalta F, Lepesheva GI J Med Chem. 2014 Jul 29. PMID:25033013[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
- ↑ Friggeri L, Hargrove TY, Rachakonda G, Williams AD, Wawrzak Z, Di Santo R, De Vita D, Waterman MR, Tortorella S, Villalta F, Lepesheva GI. Structural Basis for Rational Design of Inhibitors Targeting Trypanosoma cruzi Sterol 14alpha-Demethylase: Two Regions of the Enzyme Molecule Potentiate Its Inhibition. J Med Chem. 2014 Jul 29. PMID:25033013 doi:http://dx.doi.org/10.1021/jm500739f
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