4j57

From Proteopedia

(Difference between revisions)

Current revision

Structure of Plasmodium falciparum thioredoxin reductase-thioredoxin complex

Structural highlights

4j57 is a 4 chain structure with sequence from Plasmodium falciparum 3D7. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.5Å
Ligands:	,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

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: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 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.

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

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

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/4j57"

@@ Line 4: / Line 4: @@
 == 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='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>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.5&#8491;</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: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>
+[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 ==

4j57

From Proteopedia

Current revision

Structure of Plasmodium falciparum thioredoxin reductase-thioredoxin complex

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

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