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| - | ==TRYPANOSOMA BRUCEI TRYPANOTHIONE REDUCTASE WITH BOUND NADP.== | + | ==Trypanosoma brucei trypanothione reductase with bound NADP.== |
| - | <StructureSection load='2wov' size='340' side='right' caption='[[2wov]], [[Resolution|resolution]] 2.50Å' scene=''> | + | <StructureSection load='2wov' size='340' side='right'caption='[[2wov]], [[Resolution|resolution]] 2.50Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[2wov]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/Trypanosoma_brucei_treu927 Trypanosoma brucei treu927]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2WOV OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2WOV FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[2wov]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Trypanosoma_brucei_brucei_TREU927 Trypanosoma brucei brucei TREU927]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2WOV OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2WOV 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=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=NDP:NADPH+DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NDP</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]] 2.5Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[2woi|2woi]], [[2wow|2wow]]</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=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=NDP:NADPH+DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NDP</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=2wov FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2wov OCA], [https://pdbe.org/2wov PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2wov RCSB], [https://www.ebi.ac.uk/pdbsum/2wov PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2wov 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=2wov FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2wov OCA], [http://pdbe.org/2wov PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=2wov RCSB], [http://www.ebi.ac.uk/pdbsum/2wov PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=2wov ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | + | == Function == |
| | + | [https://www.uniprot.org/uniprot/Q389T8_TRYB2 Q389T8_TRYB2] |
| | == Evolutionary Conservation == | | == Evolutionary Conservation == |
| | [[Image:Consurf_key_small.gif|200px|right]] | | [[Image:Consurf_key_small.gif|200px|right]] |
| | Check<jmol> | | Check<jmol> |
| | <jmolCheckbox> | | <jmolCheckbox> |
| - | <scriptWhenChecked>select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/wo/2wov_consurf.spt"</scriptWhenChecked> | + | <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/wo/2wov_consurf.spt"</scriptWhenChecked> |
| - | <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked> | + | <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview03.spt</scriptWhenUnchecked> |
| | <text>to colour the structure by Evolutionary Conservation</text> | | <text>to colour the structure by Evolutionary Conservation</text> |
| | </jmolCheckbox> | | </jmolCheckbox> |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Trypanosoma brucei treu927]] | + | [[Category: Large Structures]] |
| - | [[Category: Trypanothione-disulfide reductase]] | + | [[Category: Trypanosoma brucei brucei TREU927]] |
| - | [[Category: Alphey, M S]] | + | [[Category: Alphey MS]] |
| - | [[Category: Fairlamb, A H]] | + | [[Category: Fairlamb AH]] |
| - | [[Category: Flavoprotein]]
| + | |
| - | [[Category: Oxidoreductase]]
| + | |
| - | [[Category: Redox-active center]]
| + | |
| - | [[Category: Reductase]]
| + | |
| - | [[Category: Sleeping sickness]]
| + | |
| - | [[Category: Trypanosomiasis]]
| + | |
| - | [[Category: Trypanothione]]
| + | |
| Structural highlights
Function
Q389T8_TRYB2
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 (TryR) is a genetically validated drug target in the parasite Trypanosoma brucei , the causative agent of human African trypanosomiasis. Here we report the discovery, synthesis, and development of a novel series of TryR inhibitors based on a 3,4-dihydroquinazoline scaffold. In addition, a high resolution crystal structure of TryR, alone and in complex with substrates and inhibitors from this series, is presented. This represents the first report of a high resolution complex between a noncovalent ligand and this enzyme. Structural studies revealed that upon ligand binding the enzyme undergoes a conformational change to create a new subpocket which is occupied by an aryl group on the ligand. Therefore, the inhibitor, in effect, creates its own small binding pocket within the otherwise large, solvent exposed active site. The TryR-ligand structure was subsequently used to guide the synthesis of inhibitors, including analogues that challenged the induced subpocket. This resulted in the development of inhibitors with improved potency against both TryR and T. brucei parasites in a whole cell assay.
Dihydroquinazolines as a Novel Class of Trypanosoma brucei Trypanothione Reductase Inhibitors: Discovery, Synthesis, and Characterization of their Binding Mode by Protein Crystallography.,Patterson S, Alphey MS, Jones DC, Shanks EJ, Street IP, Frearson JA, Wyatt PG, Gilbert IH, Fairlamb AH J Med Chem. 2011 Oct 13;54(19):6514-30. Epub 2011 Sep 1. PMID:21851087[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Patterson S, Alphey MS, Jones DC, Shanks EJ, Street IP, Frearson JA, Wyatt PG, Gilbert IH, Fairlamb AH. Dihydroquinazolines as a Novel Class of Trypanosoma brucei Trypanothione Reductase Inhibitors: Discovery, Synthesis, and Characterization of their Binding Mode by Protein Crystallography. J Med Chem. 2011 Oct 13;54(19):6514-30. Epub 2011 Sep 1. PMID:21851087 doi:10.1021/jm200312v
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