4j57: Difference between revisions
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==Structure of Plasmodium falciparum thioredoxin reductase-thioredoxin complex== | |||
<StructureSection load='4j57' size='340' side='right'caption='[[4j57]], [[Resolution|resolution]] 2.50Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[4j57]] is a 4 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=4J57 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4J57 FirstGlance]. <br> | |||
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.5Å</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>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene></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=4j57 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4j57 OCA], [https://pdbe.org/4j57 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4j57 RCSB], [https://www.ebi.ac.uk/pdbsum/4j57 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4j57 ProSAT]</span></td></tr> | |||
</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:11013257, PubMed:16910770, PubMed:23845423, PubMed:9368022). 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;"> | |||
== 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<ref>PMID:23845423</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 4j57" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[Thioredoxin 3D structures|Thioredoxin 3D structures]] | |||
*[[Thioredoxin reductase 3D structures|Thioredoxin reductase 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Large Structures]] | |||
[[Category: Plasmodium falciparum 3D7]] | |||
[[Category: Becker K]] | |||
[[Category: Fritz-Wolf K]] | |||
[[Category: Iozef R]] | |||
[[Category: Jortzik E]] | |||
[[Category: Preuss J]] | |||
[[Category: Rahlfs S]] | |||
[[Category: Stumpf M]] | |||
Latest revision as of 14:00, 6 November 2024
Structure of Plasmodium falciparum thioredoxin reductase-thioredoxin complexStructure of Plasmodium falciparum thioredoxin reductase-thioredoxin complex
Structural highlights
FunctionTRXR_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:11013257, PubMed:16910770, PubMed:23845423, PubMed:9368022). 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 PubMedOver 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 AlsoReferences
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