4by0: Difference between revisions
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== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[4by0]] 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=4BY0 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4BY0 FirstGlance]. <br> | <table><tr><td colspan='2'>[[4by0]] 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=4BY0 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4BY0 FirstGlance]. <br> | ||
</td></tr><tr><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=5PS:(R)-N-(3-(1H-INDOL-3-YL)-1-OXO-1-(PYRIDIN-4-YLAMINO)PROPAN-2-YL)-3,3-DIFLUORO-(1,1-BIPHENYL)-4-CARBOXAMIDE'>5PS</scene>, <scene name='pdbligand=HEM:PROTOPORPHYRIN+IX+CONTAINING+FE'>HEM</scene>< | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=5PS:(R)-N-(3-(1H-INDOL-3-YL)-1-OXO-1-(PYRIDIN-4-YLAMINO)PROPAN-2-YL)-3,3-DIFLUORO-(1,1-BIPHENYL)-4-CARBOXAMIDE'>5PS</scene>, <scene name='pdbligand=HEM:PROTOPORPHYRIN+IX+CONTAINING+FE'>HEM</scene></td></tr> | ||
<tr><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'>[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><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4by0 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4by0 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4by0 RCSB], [http://www.ebi.ac.uk/pdbsum/4by0 PDBsum]</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=4by0 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4by0 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4by0 RCSB], [http://www.ebi.ac.uk/pdbsum/4by0 PDBsum]</span></td></tr> | ||
<table> | </table> | ||
== 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] | |||
<div style="background-color:#fffaf0;"> | <div style="background-color:#fffaf0;"> | ||
== Publication Abstract from PubMed == | == Publication Abstract from PubMed == | ||
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[[Category: Sterol 14-demethylase]] | [[Category: Sterol 14-demethylase]] | ||
[[Category: Trycr]] | [[Category: Trycr]] | ||
[[Category: Calvet, C M | [[Category: Calvet, C M]] | ||
[[Category: Cameron, M D | [[Category: Cameron, M D]] | ||
[[Category: Choi, J Y | [[Category: Choi, J Y]] | ||
[[Category: Gunatilleke, S S | [[Category: Gunatilleke, S S]] | ||
[[Category: McKerrow, J H | [[Category: McKerrow, J H]] | ||
[[Category: Podust, L M | [[Category: Podust, L M]] | ||
[[Category: Roush, W R | [[Category: Roush, W R]] | ||
[[Category: Vierira, D F | [[Category: Vierira, D F]] | ||
[[Category: Chagas disease]] | [[Category: Chagas disease]] | ||
[[Category: Oxidoreductase]] | [[Category: Oxidoreductase]] | ||
[[Category: Sterol biosynthesis]] | [[Category: Sterol biosynthesis]] | ||
Revision as of 16:47, 24 December 2014
Crystal structure of Trypanosoma cruzi CYP51 bound to the inhibitor (R)-N-(3-(1H-indol-3-yl)-1-oxo-1-(pyridin-4-ylamino)propan-2-yl)-3,3'- difluoro-(1,1'-biphenyl)-4-carboxamideCrystal structure of Trypanosoma cruzi CYP51 bound to the inhibitor (R)-N-(3-(1H-indol-3-yl)-1-oxo-1-(pyridin-4-ylamino)propan-2-yl)-3,3'- difluoro-(1,1'-biphenyl)-4-carboxamide
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 PubMedSterol 14alpha-demethylase (CYP51) is an important therapeutic target for fungal and parasitic infections due to its key role in the biosynthesis of ergosterol, an essential component of the cell membranes of these pathogenic organisms. We report the development of potent and selective d-tryptophan-derived inhibitors of T. cruzi CYP51. Structural information obtained from the cocrystal structure of CYP51 and (R)-2, which is >1000-fold more potent than its enantiomer (S)-1, was used to guide design of additional analogues. The in vitro efficacy data presented here for (R)-2-(R)-8, together with preliminary in vitro pharmacokinetic data suggest that this new CYP51 inhibitor scaffold series has potential to deliver drug candidates for treatment of T. cruzi infections. R-Configuration of 4-Aminopyridyl-Based Inhibitors of CYP51 Confers Superior Efficacy Against Trypanosoma cruzi.,Choi JY, Calvet CM, Vieira DF, Gunatilleke SS, Cameron MD, McKerrow JH, Podust LM, Roush WR ACS Med Chem Lett. 2014 Jan 22;5(4):434-9. doi: 10.1021/ml500010m. eCollection, 2014 Apr 10. PMID:24900854[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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