4c28: Difference between revisions
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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)-4-(4-(4-chlorophenyl)piperazin-1-yl)-2-fluorobenzamide.== | ==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)-4-(4-(4-chlorophenyl)piperazin-1-yl)-2-fluorobenzamide.== | ||
<StructureSection load='4c28' size='340' side='right' caption='[[4c28]], [[Resolution|resolution]] 2.03Å' scene=''> | <StructureSection load='4c28' size='340' side='right'caption='[[4c28]], [[Resolution|resolution]] 2.03Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[4c28]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4C28 OCA]. For a <b>guided tour on the structure components</b> use [ | <table><tr><td colspan='2'>[[4c28]] 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=4C28 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4C28 FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><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>, <scene name='pdbligand=TW5:(R)-N-(3-(1H-INDOL-3-YL)-1-OXO-1-(PYRIDIN-4-YLAMINO)PROPAN-2-YL)-4-(4-(4-CHLOROPHENYL)PIPERAZIN-1-YL)-2-FLUOROBENZAMIDE'>TW5</scene | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.03Å</td></tr> | ||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><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>, <scene name='pdbligand=TW5:(R)-N-(3-(1H-INDOL-3-YL)-1-OXO-1-(PYRIDIN-4-YLAMINO)PROPAN-2-YL)-4-(4-(4-CHLOROPHENYL)PIPERAZIN-1-YL)-2-FLUOROBENZAMIDE'>TW5</scene></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=4c28 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4c28 OCA], [https://pdbe.org/4c28 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4c28 RCSB], [https://www.ebi.ac.uk/pdbsum/4c28 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4c28 ProSAT]</span></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[ | |||
</table> | </table> | ||
== Function == | == Function == | ||
[ | [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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</div> | </div> | ||
<div class="pdbe-citations 4c28" style="background-color:#fffaf0;"></div> | <div class="pdbe-citations 4c28" style="background-color:#fffaf0;"></div> | ||
==See Also== | |||
*[[Cytochrome P450 3D structures|Cytochrome P450 3D structures]] | |||
== References == | == References == | ||
<references/> | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: | [[Category: Large Structures]] | ||
[[Category: Calvet | [[Category: Trypanosoma cruzi]] | ||
[[Category: Cameron | [[Category: Calvet CM]] | ||
[[Category: Choi | [[Category: Cameron MD]] | ||
[[Category: Gut | [[Category: Choi JY]] | ||
[[Category: Kellar | [[Category: Gut J]] | ||
[[Category: McKerrow | [[Category: Kellar D]] | ||
[[Category: Podust | [[Category: McKerrow JH]] | ||
[[Category: Roush | [[Category: Podust LM]] | ||
[[Category: Siqueira-Neto | [[Category: Roush WR]] | ||
[[Category: Vieira | [[Category: Siqueira-Neto JL]] | ||
[[Category: Vieira DF]] | |||
Latest revision as of 15:02, 20 December 2023
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)-4-(4-(4-chlorophenyl)piperazin-1-yl)-2-fluorobenzamide.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)-4-(4-(4-chlorophenyl)piperazin-1-yl)-2-fluorobenzamide.
Structural highlights
FunctionCP51_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 PubMedChagas 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 >/=99.8% parasitemia in mice when administered orally at 25 mg/kg, b.i.d., for 4 days. 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[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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