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| | <StructureSection load='1gxf' size='340' side='right'caption='[[1gxf]], [[Resolution|resolution]] 2.70Å' scene=''> | | <StructureSection load='1gxf' size='340' side='right'caption='[[1gxf]], [[Resolution|resolution]] 2.70Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[1gxf]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Trycr Trycr]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1GXF OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1GXF FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[1gxf]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Trypanosoma_cruzi Trypanosoma cruzi]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1GXF OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1GXF 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>, <scene name='pdbligand=MAE:MALEIC+ACID'>MAE</scene>, <scene name='pdbligand=QUM:QUINACRINE+MUSTARD'>QUM</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]] 2.7Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1aog|1aog]], [[1nda|1nda]]</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=MAE:MALEIC+ACID'>MAE</scene>, <scene name='pdbligand=QUM:QUINACRINE+MUSTARD'>QUM</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=1gxf FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1gxf OCA], [https://pdbe.org/1gxf PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1gxf RCSB], [https://www.ebi.ac.uk/pdbsum/1gxf PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1gxf 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=1gxf FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1gxf OCA], [http://pdbe.org/1gxf PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=1gxf RCSB], [http://www.ebi.ac.uk/pdbsum/1gxf PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=1gxf ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/TYTR_TRYCR TYTR_TRYCR]] Trypanothione is the parasite analog of glutathione; this enzyme is the equivalent of glutathione reductase. | + | [https://www.uniprot.org/uniprot/TYTR_TRYCR TYTR_TRYCR] Trypanothione is the parasite analog of glutathione; this enzyme is the equivalent of glutathione reductase. |
| | == Evolutionary Conservation == | | == Evolutionary Conservation == |
| | [[Image:Consurf_key_small.gif|200px|right]] | | [[Image:Consurf_key_small.gif|200px|right]] |
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| | </StructureSection> | | </StructureSection> |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Trycr]] | + | [[Category: Trypanosoma cruzi]] |
| - | [[Category: Trypanothione-disulfide reductase]]
| + | [[Category: Bond CS]] |
| - | [[Category: Bond, C S]] | + | [[Category: Fairlamb AH]] |
| - | [[Category: Fairlamb, A H]] | + | [[Category: Hunter WN]] |
| - | [[Category: Hunter, W N]] | + | [[Category: Peterson MR]] |
| - | [[Category: Peterson, M R]] | + | [[Category: Vickers TJ]] |
| - | [[Category: Vickers, T J]] | + | |
| - | [[Category: Disulphide oxidoreductase]]
| + | |
| - | [[Category: Fad]]
| + | |
| - | [[Category: Fad dependent]]
| + | |
| - | [[Category: Flavoprotein]]
| + | |
| - | [[Category: Inhibitor]]
| + | |
| - | [[Category: Nadp]]
| + | |
| - | [[Category: Oxidoreductase]]
| + | |
| - | [[Category: Quinacrine mustard]]
| + | |
| - | [[Category: Redox-active center]]
| + | |
| - | [[Category: Trypanothione reductase]]
| + | |
| Structural highlights
Function
TYTR_TRYCR Trypanothione is the parasite analog of glutathione; this enzyme is the equivalent of glutathione reductase.
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
Trypanothione reductase is a key enzyme in the trypanothione-based redox metabolism of pathogenic trypanosomes. Because this system is absent in humans, being replaced with glutathione and glutathione reductase, it offers a target for selective inhibition. The rational design of potent inhibitors requires accurate structures of enzyme-inhibitor complexes, but this is lacking for trypanothione reductase. We therefore used quinacrine mustard, an alkylating derivative of the competitive inhibitor quinacrine, to probe the active site of this dimeric flavoprotein. Quinacrine mustard irreversibly inactivates Trypanosoma cruzi trypanothione reductase, but not human glutathione reductase, in a time-dependent manner with a stoichiometry of two inhibitors bound per monomer. The rate of inactivation is dependent upon the oxidation state of trypanothione reductase, with the NADPH-reduced form being inactivated significantly faster than the oxidized form. Inactivation is slowed by clomipramine and a melarsen oxide-trypanothione adduct (both are competitive inhibitors) but accelerated by quinacrine. The structure of the trypanothione reductase-quinacrine mustard adduct was determined to 2.7 A, revealing two molecules of inhibitor bound in the trypanothione-binding site. The acridine moieties interact with each other through pi-stacking effects, and one acridine interacts in a similar fashion with a tryptophan residue. These interactions provide a molecular explanation for the differing effects of clomipramine and quinacrine on inactivation by quinacrine mustard. Synergism with quinacrine occurs as a result of these planar acridines being able to stack together in the active site cleft, thereby gaining an increased number of binding interactions, whereas antagonism occurs with nonplanar molecules, such as clomipramine, where stacking is not possible.
Two interacting binding sites for quinacrine derivatives in the active site of trypanothione reductase: a template for drug design.,Saravanamuthu A, Vickers TJ, Bond CS, Peterson MR, Hunter WN, Fairlamb AH J Biol Chem. 2004 Jul 9;279(28):29493-500. Epub 2004 Apr 21. PMID:15102853[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Saravanamuthu A, Vickers TJ, Bond CS, Peterson MR, Hunter WN, Fairlamb AH. Two interacting binding sites for quinacrine derivatives in the active site of trypanothione reductase: a template for drug design. J Biol Chem. 2004 Jul 9;279(28):29493-500. Epub 2004 Apr 21. PMID:15102853 doi:10.1074/jbc.M403187200
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