6btl: Difference between revisions
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New page: '''Unreleased structure''' The entry 6btl is ON HOLD Authors: Bryson, S., De Gasparo, R., Krauth-Siegel, R.L., Diederich, F., Pai, E.F. Description: Crystal structure of Trypanothione ... |
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==Crystal structure of Trypanothione Reductase from Trypanosoma brucei in complex with inhibitor RD117 1-[2-(Piperazin-1-yl)ethyl]-5-{5-[1-(pyrrolidin-1-yl)cyclohexyl]-1,3-thiazol-2-yl}-1H-indole== | |||
<StructureSection load='6btl' size='340' side='right'caption='[[6btl]], [[Resolution|resolution]] 2.80Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[6btl]] is a 2 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=6BTL OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6BTL FirstGlance]. <br> | |||
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.797Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><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=RD7:1-[2-(piperazin-1-yl)ethyl]-5-{5-[1-(pyrrolidin-1-yl)cyclohexyl]-1,3-thiazol-2-yl}-1H-indole'>RD7</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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=6btl FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6btl OCA], [https://pdbe.org/6btl PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6btl RCSB], [https://www.ebi.ac.uk/pdbsum/6btl PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6btl ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/Q389T8_TRYB2 Q389T8_TRYB2] | |||
<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. | |||
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> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
[[Category: | <div class="pdbe-citations 6btl" style="background-color:#fffaf0;"></div> | ||
[[Category: Bryson | |||
[[Category: | ==See Also== | ||
[[Category: Diederich | *[[Trypanothione reductase|Trypanothione reductase]] | ||
[[Category: | == References == | ||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Large Structures]] | |||
[[Category: Trypanosoma brucei brucei TREU927]] | |||
[[Category: Bryson S]] | |||
[[Category: De Gasparo R]] | |||
[[Category: Diederich F]] | |||
[[Category: Krauth-Siegel RL]] | |||
[[Category: Pai EF]] | |||