6ay4

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==Naegleria fowleri CYP51-fluconazole complex==
==Naegleria fowleri CYP51-fluconazole complex==
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<StructureSection load='6ay4' size='340' side='right' caption='[[6ay4]], [[Resolution|resolution]] 2.70&Aring;' scene=''>
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<StructureSection load='6ay4' size='340' side='right'caption='[[6ay4]], [[Resolution|resolution]] 2.70&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>[[6ay4]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Brain_eating_amoeba Brain eating amoeba]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6AY4 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6AY4 FirstGlance]. <br>
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<table><tr><td colspan='2'>[[6ay4]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Naegleria_fowleri Naegleria fowleri]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6AY4 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6AY4 FirstGlance]. <br>
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=HEM:PROTOPORPHYRIN+IX+CONTAINING+FE'>HEM</scene>, <scene name='pdbligand=TPF:2-(2,4-DIFLUOROPHENYL)-1,3-DI(1H-1,2,4-TRIAZOL-1-YL)PROPAN-2-OL'>TPF</scene></td></tr>
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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]] 2.7&#8491;</td></tr>
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<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5tl8|5tl8]]</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=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=HEM:PROTOPORPHYRIN+IX+CONTAINING+FE'>HEM</scene>, <scene name='pdbligand=TPF:2-(2,4-DIFLUOROPHENYL)-1,3-DI(1H-1,2,4-TRIAZOL-1-YL)PROPAN-2-OL'>TPF</scene></td></tr>
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<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">NF0102700 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=5763 Brain eating amoeba])</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=6ay4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6ay4 OCA], [https://pdbe.org/6ay4 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6ay4 RCSB], [https://www.ebi.ac.uk/pdbsum/6ay4 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6ay4 ProSAT]</span></td></tr>
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<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=6ay4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6ay4 OCA], [http://pdbe.org/6ay4 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6ay4 RCSB], [http://www.ebi.ac.uk/pdbsum/6ay4 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6ay4 ProSAT]</span></td></tr>
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</table>
</table>
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<div style="background-color:#fffaf0;">
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== Function ==
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== Publication Abstract from PubMed ==
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[https://www.uniprot.org/uniprot/A0A2H4A2U9_NAEFO A0A2H4A2U9_NAEFO]
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Primary Amoebic Meningoencephalitis (PAM) is caused by Naegleria fowleri, a free-living amoeba that occasionally infects humans. While considered "rare" (but likely underreported) the high mortality rate and lack of established success in treatment makes PAM a particularly devastating infection. In the absence of economic inducements to invest in development of anti-PAM drugs by the pharmaceutical industry, anti-PAM drug discovery largely relies on drug 'repurposing'-a cost effective strategy to apply known drugs for treatment of rare or neglected diseases. Similar to fungi, N. fowleri has an essential requirement for ergosterol, a building block of plasma and cell membranes. Disruption of sterol biosynthesis by small-molecule inhibitors is a validated interventional strategy against fungal pathogens of medical and agricultural importance. The N. fowleri genome encodes the sterol 14-demethylase (CYP51) target sharing ~35% sequence identity to fungal orthologues. The similarity of targets raises the possibility of repurposing anti-mycotic drugs and optimization of their usage for the treatment of PAM. In this work, we (i) systematically assessed the impact of anti-fungal azole drugs, known as conazoles, on sterol biosynthesis and viability of cultured N. fowleri trophozotes, (ii) identified the endogenous CYP51 substrate by mass spectrometry analysis of N. fowleri lipids, and (iii) analyzed the interactions between the recombinant CYP51 target and conazoles by UV-vis spectroscopy and x-ray crystallography. Collectively, the target-based and parasite-based data obtained in these studies validated CYP51 as a potentially 'druggable' target in N. fowleri, and conazole drugs as the candidates for assessment in the animal model of PAM.
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CYP51 is an essential drug target for the treatment of primary amoebic meningoencephalitis (PAM).,Debnath A, Calvet CM, Jennings G, Zhou W, Aksenov A, Luth MR, Abagyan R, Nes WD, McKerrow JH, Podust LM PLoS Negl Trop Dis. 2017 Dec 28;11(12):e0006104. doi:, 10.1371/journal.pntd.0006104. eCollection 2017 Dec. PMID:29284029<ref>PMID:29284029</ref>
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==See Also==
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*[[Cytochrome P450 3D structures|Cytochrome P450 3D structures]]
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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 6ay4" style="background-color:#fffaf0;"></div>
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== References ==
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<references/>
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__TOC__
__TOC__
</StructureSection>
</StructureSection>
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[[Category: Brain eating amoeba]]
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[[Category: Large Structures]]
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[[Category: Abagyan, R]]
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[[Category: Naegleria fowleri]]
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[[Category: Aksenov, A]]
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[[Category: Abagyan R]]
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[[Category: Calvet, C M]]
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[[Category: Aksenov A]]
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[[Category: Debnath, A]]
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[[Category: Calvet CM]]
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[[Category: Jennings, G]]
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[[Category: Debnath A]]
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[[Category: Luth, M]]
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[[Category: Jennings G]]
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[[Category: McKerrow, J H]]
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[[Category: Luth M]]
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[[Category: Nes, W D]]
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[[Category: McKerrow JH]]
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[[Category: Podust, L M]]
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[[Category: Nes WD]]
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[[Category: Zhou, W]]
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[[Category: Podust LM]]
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[[Category: Cyp51]]
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[[Category: Zhou W]]
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[[Category: Oxidoreductase]]
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[[Category: Sterol 14alpha-demethylase]]
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Current revision

Naegleria fowleri CYP51-fluconazole complex

PDB ID 6ay4

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