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4c28

From Proteopedia

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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)-4-(4-(4-chlorophenyl)piperazin-1-yl)-2-fluorobenzamide.

Structural highlights

4c28 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.
Method:	X-ray diffraction, Resolution 2.03Å
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]

Publication Abstract from PubMed

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 >/=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.

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, Calvet CM, Siqueira-Neto JL, Johnston JB, Kellar D, Gut J, Cameron MD, McKerrow JH, Roush WR, Podust LM. Binding Mode and Potency of N-Indolyloxopyridinyl-4-aminopropanyl-Based Inhibitors Targeting Trypanosoma cruzi CYP51. J Med Chem. 2014 Nov 25. PMID:25393646 doi:http://dx.doi.org/10.1021/jm501568b

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 See Also
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/4c28"

@@ Line 3: / Line 3: @@
 <StructureSection load='4c28' size='340' side='right'caption='[[4c28]], [[Resolution|resolution]] 2.03&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[4c28]] 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=4C28 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4C28 FirstGlance]. <br>
+<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>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.03&#8491;</td></tr>
-<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4c27|4c27]]</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='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=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'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4c28 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4c28 OCA], [http://pdbe.org/4c28 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4c28 RCSB], [http://www.ebi.ac.uk/pdbsum/4c28 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4c28 ProSAT]</span></td></tr>
 </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]
+[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 ==
@@ Line 20: / Line 19: @@
 </div>
 <div class="pdbe-citations 4c28" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[Cytochrome P450 3D structures|Cytochrome P450 3D structures]]
 == References ==
 <references/>
@@ Line 25: / Line 27: @@
 </StructureSection>
 [[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: Gut J]]
-[[Category: Gut, J]]
+[[Category: Kellar D]]
-[[Category: Kellar, D]]
+[[Category: McKerrow JH]]
-[[Category: McKerrow, J H]]
+[[Category: Podust LM]]
-[[Category: Podust, L M]]
+[[Category: Roush WR]]
-[[Category: Roush, W R]]
+[[Category: Siqueira-Neto JL]]
-[[Category: Siqueira-Neto, J L]]
+[[Category: Vieira DF]]
-[[Category: Vieira, D F]]
-[[Category: Chagas disease]]
-[[Category: Oxidoreductase]]
-[[Category: Sterol biosynthesis]]

4c28

From Proteopedia

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)-4-(4-(4-chlorophenyl)piperazin-1-yl)-2-fluorobenzamide.

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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