4b1b: Difference between revisions

Latest revision as of 11:41, 20 December 2023

Crystal structure of Plasmodium falciparum oxidised Thioredoxin Reductase at 2.9 angstrom

Structural highlights

4b1b is a 2 chain structure with sequence from Plasmodium falciparum. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.9Å
Ligands:	FAD
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: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

Plasmodium falciparum is the vector of the most prevalent and deadly form of malaria, and, among the Plasmodium species, it is the one with the highest rate of drug resistance. At the basis of a rational drug design project there is the selection and characterization of suitable target(s). Thioredoxin reductase, the first protection against reactive oxygen species in the erythrocytic phase of the parasite, is essential for its survival. Hence it represents a good target for the design of new anti-malarial active compounds. In this paper we present the first crystal structure of recombinant P. falciparum thioredoxin reductase (PfTrxR) at 2.9A and discuss its differences with respect to the human orthologue. The most important one resides in the dimer interface, which offers a good binding site for selective non competitive inhibitors. The striking conservation of this feature among the Plasmodium parasites, but not among other Apicomplexa parasites neither in mammals, boosts its exploitability.

Crystal structure of Plasmodium falciparum thioredoxin reductase, a validated drug target.,Boumis G, Giardina G, Angelucci F, Bellelli A, Brunori M, Dimastrogiovanni D, Saccoccia F, Miele AE Biochem Biophys Res Commun. 2012 Aug 6. PMID:22889878^[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:https://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:https://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:https://dx.doi.org/10.1074/jbc.272.47.29584
↑ Boumis G, Giardina G, Angelucci F, Bellelli A, Brunori M, Dimastrogiovanni D, Saccoccia F, Miele AE. Crystal structure of Plasmodium falciparum thioredoxin reductase, a validated drug target. Biochem Biophys Res Commun. 2012 Aug 6. PMID:22889878 doi:10.1016/j.bbrc.2012.07.156

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OCA

[1] 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:https://dx.doi.org/10.1074/jbc.M007633200

[2] 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:https://dx.doi.org/10.1089/ars.2006.8.1227

[3] 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

[4] 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:https://dx.doi.org/10.1074/jbc.272.47.29584

[5] Boumis G, Giardina G, Angelucci F, Bellelli A, Brunori M, Dimastrogiovanni D, Saccoccia F, Miele AE. Crystal structure of Plasmodium falciparum thioredoxin reductase, a validated drug target. Biochem Biophys Res Commun. 2012 Aug 6. PMID:22889878 doi:10.1016/j.bbrc.2012.07.156

[1]

[2]

[3]

[4]

[5]

@@ Line 3: / Line 3: @@
 <StructureSection load='4b1b' size='340' side='right'caption='[[4b1b]], [[Resolution|resolution]] 2.90&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[4b1b]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Plafa Plafa]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4B1B OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4B1B FirstGlance]. <br>
+<table><tr><td colspan='2'>[[4b1b]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Plasmodium_falciparum Plasmodium falciparum]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4B1B OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4B1B 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></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]] 2.9&#8491;</td></tr>
-<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Thioredoxin-disulfide_reductase Thioredoxin-disulfide reductase], with EC number [https://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.8.1.9 1.8.1.9] </span></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='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4b1b FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4b1b OCA], [https://pdbe.org/4b1b PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4b1b RCSB], [https://www.ebi.ac.uk/pdbsum/4b1b PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4b1b 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>
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 25: / Line 27: @@
 </StructureSection>
 [[Category: Large Structures]]
-[[Category: Plafa]]
+[[Category: Plasmodium falciparum]]
-[[Category: Thioredoxin-disulfide reductase]]
+[[Category: Angelucci F]]
-[[Category: Angelucci, F]]
+[[Category: Bellelli A]]
-[[Category: Bellelli, A]]
+[[Category: Boumis G]]
-[[Category: Boumis, G]]
+[[Category: Brunori M]]
-[[Category: Brunori, M]]
+[[Category: Dimastrogiovanni D]]
-[[Category: Dimastrogiovanni, D]]
+[[Category: Giardina G]]
-[[Category: Giardina, G]]
+[[Category: Miele AE]]
-[[Category: Miele, A E]]
+[[Category: Saccoccia F]]
-[[Category: Saccoccia, F]]
-[[Category: Class-i pyridine nucleotide-disulfide oxidoreductase]]
-[[Category: Fad]]
-[[Category: Malaria]]
-[[Category: Nadph]]
-[[Category: Oxidoreductase]]
-[[Category: Thiol-mediated redox metabolism]]

4b1b: Difference between revisions

Latest revision as of 11:41, 20 December 2023

Crystal structure of Plasmodium falciparum oxidised Thioredoxin Reductase at 2.9 angstrom

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

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