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4ck8

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STEROL 14-ALPHA DEMETHYLASE (CYP51)FROM TRYPANOSOMA CRUZI IN COMPLEX WITH (R)-1-(2,4-dichlorophenyl)-2-(1H-imidazol-1-yl)ethyl 4-(4-(3,4- dichlorophenyl)piperazin-1-yl)phenylcarbamate (LFD)

Structural highlights

4ck8 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 2.62Å
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, which was once thought to be confined to endemic regions of Latin America, has now gone global, becoming a new worldwide challenge with no cure available. The disease is caused by the protozoan parasite Trypanosoma cruzi, which depends on the production of endogenous sterols, and therefore can be blocked by sterol 14alpha-demethylase (CYP51) inhibitors. Here we explore the spectral binding parameters, inhibitory effects on T. cruzi CYP51 activity, and antiparasitic potencies of a new set of beta-phenyl imidazoles. Comparative structural characterization of the T. cruzi CYP51 complexes with the three most potent inhibitors reveals two opposite binding modes of the compounds ((R)-6, EC50 = 1.2 nM, vs (S)-2/(S)-3, EC50 = 1.0/5.5 nM) and suggests the entrance into the CYP51 substrate access channel and the heme propionate-supporting ceiling of the binding cavity as two distinct areas of the protein that enhance molecular recognition and therefore could be used for the development of more effective antiparasitic drugs.

Structural Basis for Rational Design of Inhibitors Targeting Trypanosoma cruzi Sterol 14alpha-Demethylase: Two Regions of the Enzyme Molecule Potentiate Its Inhibition.,Friggeri L, Hargrove TY, Rachakonda G, Williams AD, Wawrzak Z, Di Santo R, De Vita D, Waterman MR, Tortorella S, Villalta F, Lepesheva GI J Med Chem. 2014 Jul 29. PMID:25033013^[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
↑ Friggeri L, Hargrove TY, Rachakonda G, Williams AD, Wawrzak Z, Di Santo R, De Vita D, Waterman MR, Tortorella S, Villalta F, Lepesheva GI. Structural Basis for Rational Design of Inhibitors Targeting Trypanosoma cruzi Sterol 14alpha-Demethylase: Two Regions of the Enzyme Molecule Potentiate Its Inhibition. J Med Chem. 2014 Jul 29. PMID:25033013 doi:http://dx.doi.org/10.1021/jm500739f

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

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/4ck8"

@@ Line 1: / Line 1: @@
 ==STEROL 14-ALPHA DEMETHYLASE (CYP51)FROM TRYPANOSOMA CRUZI IN COMPLEX WITH (R)-1-(2,4-dichlorophenyl)-2-(1H-imidazol-1-yl)ethyl 4-(4-(3,4- dichlorophenyl)piperazin-1-yl)phenylcarbamate (LFD)==
-<StructureSection load='4ck8' size='340' side='right' caption='[[4ck8]], [[Resolution|resolution]] 2.62&Aring;' scene=''>
+<StructureSection load='4ck8' size='340' side='right'caption='[[4ck8]], [[Resolution|resolution]] 2.62&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[4ck8]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4CK8 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4CK8 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[4ck8]] 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=4CK8 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4CK8 FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=HEM:PROTOPORPHYRIN+IX+CONTAINING+FE'>HEM</scene>, <scene name='pdbligand=LFD:(1R)-1-(2,4-DICHLOROPHENYL)-2-(1H-IMIDAZOL-1-YL)ETHYL+{4-[4-(3,4-DICHLOROPHENYL)PIPERAZIN-1-YL]PHENYL}CARBAMATE'>LFD</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]] 2.62&#8491;</td></tr>
-<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4ck9|4ck9]], [[4cka|4cka]]</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=HEM:PROTOPORPHYRIN+IX+CONTAINING+FE'>HEM</scene>, <scene name='pdbligand=LFD:(1R)-1-(2,4-DICHLOROPHENYL)-2-(1H-IMIDAZOL-1-YL)ETHYL+{4-[4-(3,4-DICHLOROPHENYL)PIPERAZIN-1-YL]PHENYL}CARBAMATE'>LFD</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=4ck8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4ck8 OCA], [https://pdbe.org/4ck8 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4ck8 RCSB], [https://www.ebi.ac.uk/pdbsum/4ck8 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4ck8 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=4ck8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4ck8 OCA], [http://pdbe.org/4ck8 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4ck8 RCSB], [http://www.ebi.ac.uk/pdbsum/4ck8 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4ck8 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 24: / Line 23: @@
 __TOC__
 </StructureSection>
-[[Category: Sterol 14-demethylase]]
+[[Category: Large Structures]]
-[[Category: Friggeri, L]]
+[[Category: Trypanosoma cruzi]]
-[[Category: Lepesheva, G I]]
+[[Category: Friggeri L]]
-[[Category: Tortorella, S]]
+[[Category: Lepesheva GI]]
-[[Category: Wawrzak, Z]]
+[[Category: Tortorella S]]
-[[Category: Cytochrome p450]]
+[[Category: Wawrzak Z]]
-[[Category: Cytochrome p450 fold]]
-[[Category: Endoplasmic reticulum membrane]]
-[[Category: Eukaryotic membrane]]
-[[Category: Monooxygenase]]
-[[Category: Oxidoreductase]]
-[[Category: Sterol biosynthesis]]

4ck8

From Proteopedia

Current revision

STEROL 14-ALPHA DEMETHYLASE (CYP51)FROM TRYPANOSOMA CRUZI IN COMPLEX WITH (R)-1-(2,4-dichlorophenyl)-2-(1H-imidazol-1-yl)ethyl 4-(4-(3,4- dichlorophenyl)piperazin-1-yl)phenylcarbamate (LFD)

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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