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| | ==X-ray structure of the Leishmania infantum tryopanothione reductase in complex with auranofin== | | ==X-ray structure of the Leishmania infantum tryopanothione reductase in complex with auranofin== |
| - | <StructureSection load='2yau' size='340' side='right' caption='[[2yau]], [[Resolution|resolution]] 3.50Å' scene=''> | + | <StructureSection load='2yau' size='340' side='right'caption='[[2yau]], [[Resolution|resolution]] 3.50Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[2yau]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Leiin Leiin]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2YAU OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2YAU FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[2yau]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Leishmania_infantum Leishmania infantum]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2YAU OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2YAU FirstGlance]. <br> |
| - | </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>, <scene name='pdbligand=TS8:3,4,5-TRIACETYLOXY-6-(ACETYLOXYMETHYL)OXANE-2-THIOL'>TS8</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]] 3.5Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[2x50|2x50]], [[2jk6|2jk6]], [[2w0h|2w0h]]</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>, <scene name='pdbligand=TS8:3,4,5-TRIACETYLOXY-6-(ACETYLOXYMETHYL)OXANE-2-THIOL'>TS8</scene></td></tr> |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Trypanothione-disulfide_reductase Trypanothione-disulfide reductase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.8.1.12 1.8.1.12] </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=2yau FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2yau OCA], [https://pdbe.org/2yau PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2yau RCSB], [https://www.ebi.ac.uk/pdbsum/2yau PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2yau 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=2yau FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2yau OCA], [http://pdbe.org/2yau PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=2yau RCSB], [http://www.ebi.ac.uk/pdbsum/2yau PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=2yau ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | + | == Function == |
| | + | [https://www.uniprot.org/uniprot/A4HSF7_LEIIN A4HSF7_LEIIN] |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Leiin]] | + | [[Category: Large Structures]] |
| - | [[Category: Trypanothione-disulfide reductase]] | + | [[Category: Leishmania infantum]] |
| - | [[Category: Baiocco, P]] | + | [[Category: Baiocco P]] |
| - | [[Category: Colotti, G]] | + | [[Category: Colotti G]] |
| - | [[Category: Ilari, A]] | + | [[Category: Ilari A]] |
| - | [[Category: Oxidoreductase]]
| + | |
| Structural highlights
2yau is a 2 chain structure with sequence from Leishmania infantum. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Method: | X-ray diffraction, Resolution 3.5Å |
| Ligands: | , , , , , |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Function
A4HSF7_LEIIN
Publication Abstract from PubMed
Auranofin is a gold(I)-containing drug in clinical use as an antiarthritic agent. Recent studies showed that auranofin manifests interesting antiparasitic actions very likely arising from inhibition of parasitic enzymes involved in the control of the redox metabolism. Trypanothione reductase is a key enzyme of Leishmania infantum polyamine-dependent redox metabolism, and a validated target for antileishmanial drugs. As trypanothione reductase contains a dithiol motif at its active site and gold(I) compounds are known to be highly thiophilic, we explored whether auranofin might behave as an effective enzyme inhibitor and as a potential antileishmanial agent. Notably, enzymatic assays revealed that auranofin causes indeed a pronounced enzyme inhibition. To gain a deeper insight into the molecular basis of enzyme inhibition, crystals of the auranofin-bound enzyme, in the presence of NADPH, were prepared, and the X-ray crystal structure of the auranofin-trypanothione reductase-NADPH complex was solved at 3.5 A resolution. In spite of the rather low resolution, these data were of sufficient quality as to identify the presence of the gold center and of the thiosugar of auranofin, and to locate them within the overall protein structure. Gold binds to the two active site cysteine residues of TR, i.e. Cys52 and Cys57, while the thiosugar moiety of auranofin binds to the trypanothione binding site; thus auranofin appears to inhibit TR through a dual mechanism. Auranofin kills the promastigote stage of L. infantum at micromolar concentration; these findings will contribute to the design of new drugs against leishmaniasis.
A gold-containing drug against parasitic polyamine metabolism: the X-ray structure of trypanothione reductase from Leishmania infantum in complex with auranofin reveals a dual mechanism of enzyme inhibition.,Ilari A, Baiocco P, Messori L, Fiorillo A, Boffi A, Gramiccia M, Di Muccio T, Colotti G Amino Acids. 2011 Aug 11. PMID:21833767[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Ilari A, Baiocco P, Messori L, Fiorillo A, Boffi A, Gramiccia M, Di Muccio T, Colotti G. A gold-containing drug against parasitic polyamine metabolism: the X-ray structure of trypanothione reductase from Leishmania infantum in complex with auranofin reveals a dual mechanism of enzyme inhibition. Amino Acids. 2011 Aug 11. PMID:21833767 doi:10.1007/s00726-011-0997-9
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