View source for 5sa3


==PanDDA analysis group deposition -- Crystal Structure of Trypanosoma brucei Trypanothione reductase in complex with Z2856434874==
<StructureSection load='5sa3' size='340' side='right'caption='[[5sa3]], [[Resolution|resolution]] 1.74&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[5sa3]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Trypanosoma_brucei Trypanosoma brucei]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5SA3 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5SA3 FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=BR:BROMIDE+ION'>BR</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=FAD:FLAVIN-ADENINE+DINUCLEOTIDE'>FAD</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=O0M:1-{[4-(propan-2-yl)phenyl]methyl}piperidin-4-ol'>O0M</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=5sa3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5sa3 OCA], [https://pdbe.org/5sa3 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5sa3 RCSB], [https://www.ebi.ac.uk/pdbsum/5sa3 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5sa3 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) is a key factor in the redox homeostasis of trypanosomatid parasites, critical for survival in the hostile oxidative environment generated by the host to fight infection. TR is considered an attractive target for the development of new trypanocidal agents as it is essential for parasite survival but has no close homolog in humans. However, the high efficiency and turnover of TR challenging targets since only potent inhibitors, with nanomolar IC50, can significantly affect parasite redox state and viability. To aid the design of effective compounds targeting TR, we performed a fragment-based crystal screening at the Diamond Light Source XChem facility using a library optimized for follow-up synthesis steps. The experiment, allowing for testing over 300 compounds, resulted in the identification of 12 new ligands binding five different sites. Interestingly, the screening revealed the existence of an allosteric pocket close to the NADPH binding site, named the "doorstop pocket" since ligands binding at this site interfere with TR activity by hampering the "opening movement" needed to allow cofactor binding. The second remarkable site, known as the Z-site, identified by the screening, is located within the large trypanothione cavity but corresponds to a region not yet exploited for inhibition. The fragments binding to this site are close to each other and have some remarkable features making them ideal for follow-up optimization as a piperazine moiety in three out of five fragments.

Innovative Approach for a Classic Target: Fragment Screening on Trypanothione Reductase Reveals New Opportunities for Drug Design.,Fiorillo A, Colotti G, Exertier C, Liuzzi A, Seghetti F, Salerno A, Caciolla J, Ilari A Front Mol Biosci. 2022 Jul 4;9:900882. doi: 10.3389/fmolb.2022.900882. , eCollection 2022. PMID:35860359<ref>PMID:35860359</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 5sa3" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Large Structures]]
[[Category: Trypanosoma brucei]]
[[Category: Fiorillo A]]
[[Category: Ilari A]]