4by0: Difference between revisions

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<StructureSection load='4by0' size='340' side='right'caption='[[4by0]], [[Resolution|resolution]] 3.10&Aring;' scene=''>
<StructureSection load='4by0' size='340' side='right'caption='[[4by0]], [[Resolution|resolution]] 3.10&Aring;' scene=''>
== 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 [https://en.wikipedia.org/wiki/Trypanosoma_cruzi Trypanosoma cruzi]. 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 [https://proteopedia.org/fgij/fg.htm?mol=4BY0 FirstGlance]. <br>
</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>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><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='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=4by0 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4by0 OCA], [https://pdbe.org/4by0 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4by0 RCSB], [https://www.ebi.ac.uk/pdbsum/4by0 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4by0 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=4by0 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4by0 OCA], [http://pdbe.org/4by0 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4by0 RCSB], [http://www.ebi.ac.uk/pdbsum/4by0 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4by0 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;">
== Publication Abstract from PubMed ==
Sterol 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 &gt;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<ref>PMID:24900854</ref>
 
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 4by0" style="background-color:#fffaf0;"></div>
== References ==
== References ==
<references/>
<references/>
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</StructureSection>
</StructureSection>
[[Category: Large Structures]]
[[Category: Large Structures]]
[[Category: Sterol 14-demethylase]]
[[Category: Trypanosoma cruzi]]
[[Category: Trycr]]
[[Category: Calvet CM]]
[[Category: Calvet, C M]]
[[Category: Cameron MD]]
[[Category: Cameron, M D]]
[[Category: Choi JY]]
[[Category: Choi, J Y]]
[[Category: Gunatilleke SS]]
[[Category: Gunatilleke, S S]]
[[Category: McKerrow JH]]
[[Category: McKerrow, J H]]
[[Category: Podust LM]]
[[Category: Podust, L M]]
[[Category: Roush WR]]
[[Category: Roush, W R]]
[[Category: Vierira DF]]
[[Category: Vierira, D F]]
[[Category: Chagas disease]]
[[Category: Oxidoreductase]]
[[Category: Sterol biosynthesis]]

Revision as of 20:15, 7 September 2022

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

4by0 is a 2 chain structure with sequence from Trypanosoma cruzi. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:,
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

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]

References

  1. ↑ 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

4by0, resolution 3.10Å

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