6bu7: Difference between revisions

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'''Unreleased structure'''


The entry 6bu7 is ON HOLD  until Paper Publication
==Crystal structure of Trypanothione Reductase from Trypanosoma brucei in complex with inhibitor RD130 1-[2-(Piperidin-4-yl)ethyl]-5-{5-[1-(pyrrolidin-1-yl)cyclohexyl]-1,3-thiazol-2-yl}-1H-indole==
<StructureSection load='6bu7' size='340' side='right' caption='[[6bu7]], [[Resolution|resolution]] 2.73&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[6bu7]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6BU7 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6BU7 FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=EPE:4-(2-HYDROXYETHYL)-1-PIPERAZINE+ETHANESULFONIC+ACID'>EPE</scene>, <scene name='pdbligand=FAD:FLAVIN-ADENINE+DINUCLEOTIDE'>FAD</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=RD0:1-[2-(piperidin-4-yl)ethyl]-5-{5-[1-(pyrrolidin-1-yl)cyclohexyl]-1,3-thiazol-2-yl}-1H-indole'>RD0</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4nev|4nev]], [[6btl|6btl]]</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'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6bu7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6bu7 OCA], [http://pdbe.org/6bu7 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6bu7 RCSB], [http://www.ebi.ac.uk/pdbsum/6bu7 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6bu7 ProSAT]</span></td></tr>
</table>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
The tropical diseases human African trypanosomiasis, Chagas disease, and the various forms of leishmaniasis are caused by parasites of the family of trypanosomatids. These protozoa possess a unique redox metabolism based on trypanothione and trypanothione reductase (TR), making TR a promising drug target. We report the optimization of properties and potency of cyclohexylpyrrolidine inhibitors of TR by structure-based design. The best inhibitors were freely soluble and showed competitive inhibition constants (Ki ) against Trypanosoma (T.) brucei TR and T. cruzi TR and in vitro activities (half-maximal inhibitory concentration, IC50 ) against these parasites in the low micromolar range, with high selectivity against human glutathione reductase. X-ray co-crystal structures confirmed the binding of the ligands to the hydrophobic wall of the "mepacrine binding site" with the new, solubility-providing vectors oriented toward the surface of the large active site.


Authors: Bryson, S., De Gasparo, R., Krauth-Siegel, R.L., Diederich, F., Pai, E.F.
Biological Evaluation and X-ray Co-crystal Structures of Cyclohexylpyrrolidine Ligands for Trypanothione Reductase, an Enzyme from the Redox Metabolism of Trypanosoma.,De Gasparo R, Brodbeck-Persch E, Bryson S, Hentzen NB, Kaiser M, Pai EF, Krauth-Siegel RL, Diederich F ChemMedChem. 2018 May 8;13(9):957-967. doi: 10.1002/cmdc.201800067. Epub 2018 Apr, 6. PMID:29624890<ref>PMID:29624890</ref>


Description: Crystal structure of Trypanothione Reductase from Trypanosoma brucei in complex with inhibitor RD130 1-[2-(Piperidin-4-yl)ethyl]-5-{5-[1-(pyrrolidin-1-yl)cyclohexyl]-1,3-thiazol-2-yl}-1H-indole
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
[[Category: Unreleased Structures]]
</div>
[[Category: Pai, E.F]]
<div class="pdbe-citations 6bu7" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Trypanothione-disulfide reductase]]
[[Category: Bryson, S]]
[[Category: Bryson, S]]
[[Category: Krauth-Siegel, R.L]]
[[Category: De Gasparo, R]]
[[Category: Diederich, F]]
[[Category: Diederich, F]]
[[Category: Gasparo, R De]]
[[Category: Krauth-Siegel, R L]]
[[Category: Pai, E F]]
[[Category: Complex]]
[[Category: Inhibitor]]
[[Category: Oxidoreductase-inhibitor complex]]
[[Category: Sleeping sickness]]
[[Category: Trypanosoma]]
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