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| | <StructureSection load='4coh' size='340' side='right'caption='[[4coh]], [[Resolution|resolution]] 2.08Å' scene=''> | | <StructureSection load='4coh' size='340' side='right'caption='[[4coh]], [[Resolution|resolution]] 2.08Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4coh]] is a 2 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=4COH OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4COH FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4coh]] is a 2 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=4COH OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4COH 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=T9H:2-FLUORANYL-N-[(2R)-3-(1H-INDOL-3-YL)-1-OXIDANYLIDENE-1-(PYRIDIN-4-YLAMINO)PROPAN-2-YL]-4-(4-THIOPHEN-2-YLSULFONYLPIPERAZIN-1-YL)BENZAMIDE'>T9H</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=T9H:2-FLUORANYL-N-[(2R)-3-(1H-INDOL-3-YL)-1-OXIDANYLIDENE-1-(PYRIDIN-4-YLAMINO)PROPAN-2-YL]-4-(4-THIOPHEN-2-YLSULFONYLPIPERAZIN-1-YL)BENZAMIDE'>T9H</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=4coh FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4coh OCA], [https://pdbe.org/4coh PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4coh RCSB], [https://www.ebi.ac.uk/pdbsum/4coh PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4coh 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=4coh FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4coh OCA], [http://pdbe.org/4coh PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4coh RCSB], [http://www.ebi.ac.uk/pdbsum/4coh PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4coh 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 == |
| Line 24: |
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| | </StructureSection> | | </StructureSection> |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Sterol 14-demethylase]] | + | [[Category: Trypanosoma cruzi]] |
| - | [[Category: Trycr]]
| + | [[Category: Choi JY]] |
| - | [[Category: Choi, J Y]] | + | [[Category: Podust LM]] |
| - | [[Category: Podust, L M]] | + | [[Category: Roush WR]] |
| - | [[Category: Roush, W R]] | + | [[Category: Vieira DF]] |
| - | [[Category: Vieira, D F]] | + | |
| - | [[Category: Chagas disease]]
| + | |
| - | [[Category: Cyp51]]
| + | |
| - | [[Category: Sterol biosynthesis]]
| + | |
| - | [[Category: Transferase]]
| + | |
| 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 is a chronic infection caused by the protozoan parasite Trypanosoma cruzi, manifested in progressive cardiomyopathy and/or gastrointestinal dysfunction. Therapeutic options to prevent or treat Chagas disease are limited. CYP51, the enzyme key to the biosynthesis of eukaryotic membrane sterols, is a validated drug target in both fungi and T. cruzi. Sulfonamide derivatives of 4-aminopyridyl-based inhibitors of T. cruzi CYP51 (TcCYP51), including the sub-nanomolar compound 3, have molecular structures distinct from other validated CYP51 inhibitors. They augment the biologically relevant chemical space of molecules targeting TcCYP51. In a 2.08 A X-ray structure, TcCYP51 is in a conformation that has been influenced by compound 3 and is distinct from the previously characterized ground-state conformation of CYP51 drug-target complexes. That the binding site was modulated in response to an incoming inhibitor for the first time characterizes TcCYP51 as a flexible target rather than a rigid template.
Expanding the Binding Envelope of CYP51 Inhibitors Targeting Trypanosoma cruzi with 4-Aminopyridyl-Based Sulfonamide Derivatives.,Vieira DF, Choi JY, Roush WR, Podust LM Chembiochem. 2014 Apr 25. doi: 10.1002/cbic.201402027. PMID:24771705[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
- ↑ Vieira DF, Choi JY, Roush WR, Podust LM. Expanding the Binding Envelope of CYP51 Inhibitors Targeting Trypanosoma cruzi with 4-Aminopyridyl-Based Sulfonamide Derivatives. Chembiochem. 2014 Apr 25. doi: 10.1002/cbic.201402027. PMID:24771705 doi:http://dx.doi.org/10.1002/cbic.201402027
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