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| | ==Structure of Plasmodium falciparum thioredoxin reductase-thioredoxin complex== | | ==Structure of Plasmodium falciparum thioredoxin reductase-thioredoxin complex== |
| - | <StructureSection load='4j56' size='340' side='right' caption='[[4j56]], [[Resolution|resolution]] 2.37Å' scene=''> | + | <StructureSection load='4j56' size='340' side='right'caption='[[4j56]], [[Resolution|resolution]] 2.37Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4j56]] is a 8 chain structure with sequence from [http://en.wikipedia.org/wiki/Plasmodium_falciparum_3d7 Plasmodium falciparum 3d7]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4J56 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4J56 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4j56]] is a 8 chain structure with sequence from [https://en.wikipedia.org/wiki/Plasmodium_falciparum_3D7 Plasmodium falciparum 3D7]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4J56 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4J56 FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=FAD:FLAVIN-ADENINE+DINUCLEOTIDE'>FAD</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]] 2.371Å</td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">trxr2, PFI1170c ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=36329 Plasmodium falciparum 3D7]), PF14_0545 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=36329 Plasmodium falciparum 3D7])</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=FAD:FLAVIN-ADENINE+DINUCLEOTIDE'>FAD</scene></td></tr> |
| - | <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> | + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4j56 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4j56 OCA], [https://pdbe.org/4j56 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4j56 RCSB], [https://www.ebi.ac.uk/pdbsum/4j56 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4j56 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=4j56 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4j56 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4j56 RCSB], [http://www.ebi.ac.uk/pdbsum/4j56 PDBsum]</span></td></tr> | + | |
| | </table> | | </table> |
| | + | == Function == |
| | + | [https://www.uniprot.org/uniprot/TRXR_PLAF7 TRXR_PLAF7] Catalyzes the transfer of electrons from NADPH to thioredoxins TRX1, TRX2 and TRX3, which in turn act as reductants of disulfide containing proteins (PubMed:9368022, PubMed:11013257, PubMed:16910770, PubMed:23845423). Able to reduce nitroglutathione (GSNO), a compound involved in the transport of nitric oxide (NO); however, TRX1 is more efficient in reducing GSNO (PubMed:11013257). Has no catalytic activity towards oxidized glutathione (GSSG) (PubMed:11013257).<ref>PMID:11013257</ref> <ref>PMID:16910770</ref> <ref>PMID:23845423</ref> <ref>PMID:9368022</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> |
| | </div> | | </div> |
| | + | <div class="pdbe-citations 4j56" style="background-color:#fffaf0;"></div> |
| | | | |
| | ==See Also== | | ==See Also== |
| - | *[[Thioredoxin|Thioredoxin]] | + | *[[Thioredoxin 3D structures|Thioredoxin 3D structures]] |
| - | *[[Thioredoxin Reductase|Thioredoxin Reductase]] | + | *[[Thioredoxin reductase 3D structures|Thioredoxin reductase 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Plasmodium falciparum 3d7]] | + | [[Category: Large Structures]] |
| - | [[Category: Thioredoxin-disulfide reductase]] | + | [[Category: Plasmodium falciparum 3D7]] |
| - | [[Category: Becker, K]] | + | [[Category: Becker K]] |
| - | [[Category: Fritz-Wolf, K]] | + | [[Category: Fritz-Wolf K]] |
| - | [[Category: Iozef, R]] | + | [[Category: Iozef R]] |
| - | [[Category: Jortzik, E]] | + | [[Category: Jortzik E]] |
| - | [[Category: Preuss, J]] | + | [[Category: Preuss J]] |
| - | [[Category: Rahlfs, S]] | + | [[Category: Rahlfs S]] |
| - | [[Category: Stumpf, M]] | + | [[Category: Stumpf M]] |
| - | [[Category: Disulfide reductase]]
| + | |
| - | [[Category: Fad binding]]
| + | |
| - | [[Category: Nadph binding]]
| + | |
| - | [[Category: Oxidoreductase]]
| + | |
| - | [[Category: Protein-protein complex]]
| + | |
| - | [[Category: Thioredoxin binding]]
| + | |
| - | [[Category: Thioredoxin fold]]
| + | |
| Structural highlights
Function
TRXR_PLAF7 Catalyzes the transfer of electrons from NADPH to thioredoxins TRX1, TRX2 and TRX3, which in turn act as reductants of disulfide containing proteins (PubMed:9368022, PubMed:11013257, PubMed:16910770, PubMed:23845423). Able to reduce nitroglutathione (GSNO), a compound involved in the transport of nitric oxide (NO); however, TRX1 is more efficient in reducing GSNO (PubMed:11013257). Has no catalytic activity towards oxidized glutathione (GSSG) (PubMed:11013257).[1] [2] [3] [4]
Publication Abstract from PubMed
Over the last decades, malaria parasites have been rapidly developing resistance against antimalarial drugs, which underlines the need for novel drug targets. Thioredoxin reductase (TrxR) is crucially involved in redox homeostasis and essential for Plasmodium falciparum. Here, we report the first crystal structure of P. falciparum TrxR bound to its substrate thioredoxin 1. Upon complex formation, the flexible C-terminal arm and an insertion loop of PfTrxR are rearranged, suggesting that the C-terminal arm changes its conformation during catalysis similar to human TrxR. Striking differences between P. falciparum and human TrxR are a Plasmodium-specific insertion and the conformation of the C-terminal arm, which lead to considerable differences in thioredoxin binding and disulfide reduction. Moreover, we functionally analyzed amino acid residues involved in substrate binding and in the architecture of the intersubunit cavity, which is a known binding site for disulfide reductase inhibitors. Cell biological experiments indicate that P. falciparum TrxR is indeed targeted in the parasite by specific inhibitors with antimalarial activity. Differences between P. falciparum and human TrxR and details on substrate reduction and inhibitor binding provide the first solid basis for structure-based drug development and lead optimization.
Crystal Structure of the Plasmodium falciparum Thioredoxin Reductase-Thioredoxin Complex.,Fritz-Wolf K, Jortzik E, Stumpf M, Preuss J, Iozef R, Rahlfs S, Becker K J Mol Biol. 2013 Jul 9. pii: S0022-2836(13)00432-4. doi:, 10.1016/j.jmb.2013.06.037. PMID:23845423[5]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Kanzok SM, Schirmer RH, Turbachova I, Iozef R, Becker K. The thioredoxin system of the malaria parasite Plasmodium falciparum. Glutathione reduction revisited. J Biol Chem. 2000 Dec 22;275(51):40180-6. doi: 10.1074/jbc.M007633200. PMID:11013257 doi:http://dx.doi.org/10.1074/jbc.M007633200
- ↑ Nickel C, Rahlfs S, Deponte M, Koncarevic S, Becker K. Thioredoxin networks in the malarial parasite Plasmodium falciparum. Antioxid Redox Signal. 2006 Jul-Aug;8(7-8):1227-39. doi: 10.1089/ars.2006.8.1227. PMID:16910770 doi:http://dx.doi.org/10.1089/ars.2006.8.1227
- ↑ Fritz-Wolf K, Jortzik E, Stumpf M, Preuss J, Iozef R, Rahlfs S, Becker K. Crystal Structure of the Plasmodium falciparum Thioredoxin Reductase-Thioredoxin Complex. J Mol Biol. 2013 Jul 9. pii: S0022-2836(13)00432-4. doi:, 10.1016/j.jmb.2013.06.037. PMID:23845423 doi:10.1016/j.jmb.2013.06.037
- ↑ Gilberger TW, Walter RD, Muller S. Identification and characterization of the functional amino acids at the active site of the large thioredoxin reductase from Plasmodium falciparum. J Biol Chem. 1997 Nov 21;272(47):29584-9. doi: 10.1074/jbc.272.47.29584. PMID:9368022 doi:http://dx.doi.org/10.1074/jbc.272.47.29584
- ↑ Fritz-Wolf K, Jortzik E, Stumpf M, Preuss J, Iozef R, Rahlfs S, Becker K. Crystal Structure of the Plasmodium falciparum Thioredoxin Reductase-Thioredoxin Complex. J Mol Biol. 2013 Jul 9. pii: S0022-2836(13)00432-4. doi:, 10.1016/j.jmb.2013.06.037. PMID:23845423 doi:10.1016/j.jmb.2013.06.037
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