View source for 6oex


==Crystal structure of Trypanothione Reductase from Trypanosoma brucei in complex with inhibitor 3-(2-{1-[2-(Piperidin-4-yl)ethyl]-1H-indol-5-yl}-5-[1-(pyrrolidin-1-yl)cyclohexyl]-1,3- thiazol-4-yl)-N-(2,2,2-trifluoroethyl)prop-2-yn-1-amine==
<StructureSection load='6oex' size='340' side='right'caption='[[6oex]], [[Resolution|resolution]] 2.10&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[6oex]] 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=6OEX OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6OEX 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]] 2.1&#8491;</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=M9Y:3-[2-[1-(2-piperidin-4-ylethyl)indol-5-yl]-5-(1-pyrrolidin-1-ylcyclohexyl)-1,3-thiazol-4-yl]-~{N}-[2,2,2-tris(fluoranyl)ethyl]prop-2-yn-1-amine'>M9Y</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=6oex FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6oex OCA], [https://pdbe.org/6oex PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6oex RCSB], [https://www.ebi.ac.uk/pdbsum/6oex PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6oex ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/Q389T8_TRYB2 Q389T8_TRYB2] 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Trypanothione reductase (TR) plays a key role in the unique redox metabolism of trypanosomatids, the causative agents of human African trypanosomiasis (HAT), Chagas' disease, and leishmaniases. Introduction of a new, lean propargylic vector to a known class of TR inhibitors resulted in the strongest reported competitive inhibitor of Trypanosoma (T.) brucei TR, with an inhibition constant Ki of 73 nm, which is fully selective against human glutathione reductase (hGR). The best ligands exhibited in vitro IC50 values (half-maximal inhibitory concentration) against the HAT pathogen, T. brucei rhodesiense, in the mid-nanomolar range, reaching down to 50 nm. X-Ray co-crystal structures confirmed the binding mode of the ligands and revealed the presence of a HEPES buffer molecule in the large active site. Extension of the propargylic vector, guided by structure-based design, to replace the HEPES buffer molecule should give inhibitors with low nanomolar Ki and IC50 values for in vivo studies.

Targeting a Large Active Site: Structure-Based Design of Nanomolar Inhibitors of Trypanosoma brucei Trypanothione Reductase.,De Gasparo R, Halgas O, Harangozo D, Kaiser M, Pai EF, Krauth-Siegel RL, Diederich F Chemistry. 2019 Aug 13. doi: 10.1002/chem.201901664. PMID:31407832<ref>PMID:31407832</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 6oex" style="background-color:#fffaf0;"></div>

==See Also==
*[[Trypanothione reductase|Trypanothione reductase]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Large Structures]]
[[Category: Trypanosoma brucei brucei TREU927]]
[[Category: De Gasparo R]]
[[Category: Diederich F]]
[[Category: Halgas O]]
[[Category: Harangozo D]]
[[Category: Krauth-Siegel RL]]
[[Category: Pai EF]]