4c27

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(New page: '''Unreleased structure''' The entry 4c27 is ON HOLD until Paper Publication Authors: Vieira, D.F., Calvet, C.M., Choi, J.Y., Cameron, M.D., Gut, J., Kellar, D., Siqueira-Neto, J.L., Mc...)
Current revision (12:02, 20 December 2023) (edit) (undo)
 
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'''Unreleased structure'''
 
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The entry 4c27 is ON HOLD until Paper Publication
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==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)-2-fluoro-4-(4-(4-(trifluoromethyl)phenyl)piperazin-1-yl)benzamide==
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<StructureSection load='4c27' size='340' side='right'caption='[[4c27]], [[Resolution|resolution]] 1.95&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[4c27]] 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=4C27 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4C27 FirstGlance]. <br>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.95&#8491;</td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=26N:NALPHA-(2-FLUORO-4-{4-[4-(TRIFLUOROMETHYL)PHENYL]PIPERAZIN-1-YL}BENZOYL)-N-PYRIDIN-4-YL-D-TRYPTOPHANAMIDE'>26N</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=HEM:PROTOPORPHYRIN+IX+CONTAINING+FE'>HEM</scene></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4c27 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4c27 OCA], [https://pdbe.org/4c27 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4c27 RCSB], [https://www.ebi.ac.uk/pdbsum/4c27 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4c27 ProSAT]</span></td></tr>
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</table>
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== Function ==
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[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]
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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Chagas disease is a chronic infection in humans caused by Trypanosoma cruzi and manifested in progressive cardiomyopathy and/or gastrointestinal dysfunction. Limited therapeutic options to prevent and treat Chagas disease put 8 million people infected with T. cruzi worldwide at risk. CYP51, involved in the biosynthesis of the membrane sterol component in eukaryotes, is a promising drug target in T. cruzi. We report the structure-activity relationships (SAR) of an N-arylpiperazine series of N-indolyloxopyridinyl-4-aminopropanyl-based inhibitors designed to probe the impact of substituents in the terminal N-phenyl ring on binding mode, selectivity and potency. Depending on the substituents at C-4, two distinct ring binding modes, buried and solvent-exposed, have been observed by X-ray structure analysis (resolution of 1.95-2.48 A). The 5-chloro-substituted analogs 9 and 10 with no substituent at C-4 demonstrated improved selectivity and potency, suppressing &gt;/=99.8% parasitemia in mice when administered orally at 25 mg/kg, b.i.d., for 4 days.
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Authors: Vieira, D.F., Calvet, C.M., Choi, J.Y., Cameron, M.D., Gut, J., Kellar, D., Siqueira-Neto, J.L., McKerrow, J.H., Roush, W.R., Podust, L.M.
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Binding Mode and Potency of N-Indolyloxopyridinyl-4-aminopropanyl-Based Inhibitors Targeting Trypanosoma cruzi CYP51.,Vieira DF, Choi JY, Calvet CM, Siqueira-Neto JL, Johnston JB, Kellar D, Gut J, Cameron MD, McKerrow JH, Roush WR, Podust LM J Med Chem. 2014 Nov 25. PMID:25393646<ref>PMID:25393646</ref>
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Description: 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)-2-fluoro-4-(4-(4-(trifluoromethyl)phenyl)piperazin-1-yl)benzamide
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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</div>
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<div class="pdbe-citations 4c27" style="background-color:#fffaf0;"></div>
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==See Also==
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*[[Cytochrome P450 3D structures|Cytochrome P450 3D structures]]
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== References ==
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<references/>
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__TOC__
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</StructureSection>
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[[Category: Large Structures]]
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[[Category: Trypanosoma cruzi]]
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[[Category: Calvet CM]]
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[[Category: Cameron MD]]
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[[Category: Choi JY]]
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[[Category: Gut J]]
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[[Category: Kellar D]]
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[[Category: McKerrow JH]]
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[[Category: Podust LM]]
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[[Category: Roush WR]]
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[[Category: Siqueira-Neto JL]]
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[[Category: Vieira DF]]

Current revision

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)-2-fluoro-4-(4-(4-(trifluoromethyl)phenyl)piperazin-1-yl)benzamide

PDB ID 4c27

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