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4cbq

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<StructureSection load='4cbq' size='340' side='right'caption='[[4cbq]], [[Resolution|resolution]] 1.94&Aring;' scene=''>
<StructureSection load='4cbq' size='340' side='right'caption='[[4cbq]], [[Resolution|resolution]] 1.94&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>[[4cbq]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Enthi Enthi]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4CBQ OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4CBQ FirstGlance]. <br>
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<table><tr><td colspan='2'>[[4cbq]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Entamoeba_histolytica Entamoeba histolytica]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4CBQ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4CBQ 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=AU:GOLD+ION'>AU</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=FAD:FLAVIN-ADENINE+DINUCLEOTIDE'>FAD</scene>, <scene name='pdbligand=NDP:NADPH+DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NDP</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=AU:GOLD+ION'>AU</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=FAD:FLAVIN-ADENINE+DINUCLEOTIDE'>FAD</scene>, <scene name='pdbligand=NDP:NADPH+DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NDP</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
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<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Thioredoxin-disulfide_reductase Thioredoxin-disulfide reductase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.8.1.9 1.8.1.9] </span></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=4cbq FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4cbq OCA], [https://pdbe.org/4cbq PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4cbq RCSB], [https://www.ebi.ac.uk/pdbsum/4cbq PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4cbq 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=4cbq FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4cbq OCA], [http://pdbe.org/4cbq PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4cbq RCSB], [http://www.ebi.ac.uk/pdbsum/4cbq PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4cbq 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/C4LW95_ENTHI C4LW95_ENTHI]]
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The anti-arthritic gold-containing drug Auranofin is lethal to the protozoan intestinal parasite Entamoeba histolytica, the causative agent of human amebiasis, in both culture and animal models of the disease. A putative mechanism of Auranofin action proposes that monovalent gold, Au(I), released from the drug, can bind to the redox-active dithiol group of thioredoxin reductase (TrxR). Au(I) binding in the active site is expected to prevent electron transfer to the downstream substrate thioredoxin (Trx), thus interfering with redox homeostasis in the parasite. To clarify the molecular mechanism of Auranofin action in more detail, we determined a series of atomic resolution x-ray structures for E. histolytica thioredoxin (EhTrx) and thioredoxin reductase (EhTrxR), the latter with and without Auranofin. Only the disulfide-bonded form of the active site dithiol (Cys140-Cys143) was invariably observed in crystals of EhTrxR in spite of the addition of reductants in various crystallization trials, and no gold was found associated with these cysteines. Non-catalytic Cys286 was identified as the only site of modification, but further mutagenesis studies using the C286Q mutant demonstrated that this site was not responsible for inhibition of EhTrxR by Auranofin. Interestingly, we obtained both of the catalytically-relevant conformations of this bacterial-like, low molecular weight TrxR in crystals without requiring an engineered disulfide linkage between Cys mutants of TrxR and Trx (as was originally done with E. coli TrxR and Trx). We note that the -CXXC- catalytic motif, even if reduced, would likely not provide space sufficient to bind Au(I) by both cysteines of the dithiol group.
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X-ray structures of thioredoxin and thioredoxin reductase from Entamoeba histolytica and prevailing hypothesis of the mechanism of Auranofin action.,Parsonage D, Sheng F, Hirata K, Debnath A, McKerrow JH, Reed SL, Abagyan R, Poole LB, Podust LM J Struct Biol. 2016 Feb 11. pii: S1047-8477(16)30030-2. doi:, 10.1016/j.jsb.2016.02.015. PMID:26876147<ref>PMID:26876147</ref>
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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 4cbq" style="background-color:#fffaf0;"></div>
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==See Also==
==See Also==
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*[[Thioredoxin Reductase|Thioredoxin Reductase]]
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*[[Thioredoxin reductase 3D structures|Thioredoxin reductase 3D structures]]
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== References ==
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<references/>
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__TOC__
__TOC__
</StructureSection>
</StructureSection>
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[[Category: Enthi]]
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[[Category: Entamoeba histolytica]]
[[Category: Large Structures]]
[[Category: Large Structures]]
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[[Category: Thioredoxin-disulfide reductase]]
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[[Category: Debnath A]]
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[[Category: Debnath, A]]
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[[Category: Hirata K]]
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[[Category: Hirata, K]]
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[[Category: Kells PM]]
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[[Category: Kells, P M]]
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[[Category: McKerrow JH]]
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[[Category: McKerrow, J H]]
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[[Category: Parsonage D]]
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[[Category: Parsonage, D]]
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[[Category: Podust LM]]
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[[Category: Podust, L M]]
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[[Category: Poole LB]]
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[[Category: Poole, L B]]
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[[Category: Reed SL]]
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[[Category: Reed, S L]]
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[[Category: Amoebiasis]]
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[[Category: Oxidative stress]]
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[[Category: Oxidoreductase]]
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[[Category: Redox metabolism]]
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Revision as of 17:37, 7 September 2022

Crystal structure of the thioredoxin reductase from Entamoeba histolytica with auranofin Au(I) bound to Cys286

PDB ID 4cbq

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