View source for 6fmu


==Thioredoxin glutathione reductase from Schistosome mansoni in complex with 2-[4-(4-amino-butyl)-piperazin-1-yl]-ethanol==
<StructureSection load='6fmu' size='340' side='right'caption='[[6fmu]], [[Resolution|resolution]] 1.80&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[6fmu]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Schistosoma_mansoni Schistosoma mansoni]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6FMU OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6FMU 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]] 1.8&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=DVK:2-[4-(4-azanylbutyl)piperazin-1-yl]ethanol'>DVK</scene>, <scene name='pdbligand=FAD:FLAVIN-ADENINE+DINUCLEOTIDE'>FAD</scene>, <scene name='pdbligand=PGE:TRIETHYLENE+GLYCOL'>PGE</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=6fmu FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6fmu OCA], [https://pdbe.org/6fmu PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6fmu RCSB], [https://www.ebi.ac.uk/pdbsum/6fmu PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6fmu ProSAT]</span></td></tr>
</table>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Members of the FAD/NAD-linked reductase family are recognized as crucial targets in drug development for cancers, inflammatory disorders, and infectious diseases. However, individual FAD/NAD reductases are difficult to inhibit in a selective manner with off target inhibition reducing usefulness of identified compounds. Thioredoxin glutathione reductase (TGR), a high molecular weight thioredoxin reductase-like enzyme, has emerged as a promising drug target for the treatment of schistosomiasis, a parasitosis afflicting more than 200 million people. Taking advantage of small molecules selected from a high-throughput screen and using X-ray crystallography, functional assays, and docking studies, we identify a critical secondary site of the enzyme. Compounds binding at this site interfere with well-known and conserved conformational changes associated with NADPH reduction, acting as a doorstop for cofactor entry. They selectivity inhibit TGR from Schistosoma mansoni and are active against parasites in culture. Since many members of the FAD/NAD-linked reductase family have similar catalytic mechanisms the unique mechanism of inhibition identified in this study for TGR broadly opens new routes to selectively inhibit homologous enzymes of central importance in numerous diseases.

Fragment-Based Discovery of a Regulatory Site in Thioredoxin Glutathione Reductase Acting as "Doorstop" for NADPH Entry.,Silvestri I, Lyu H, Fata F, Boumis G, Miele AE, Ardini M, Ippoliti R, Bellelli A, Jadhav A, Lea WA, Simeonov A, Chen Q, Arner ESJ, Thatcher GR, Petukhov PA, Williams DL, Angelucci F ACS Chem Biol. 2018 May 25. doi: 10.1021/acschembio.8b00349. PMID:29800515<ref>PMID:29800515</ref>

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

==See Also==
*[[Thioredoxin Glutathione Reductase|Thioredoxin Glutathione Reductase]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Large Structures]]
[[Category: Schistosoma mansoni]]
[[Category: Angelucci F]]
[[Category: Boumis G]]
[[Category: Fata F]]
[[Category: MIele AE]]
[[Category: Silvestri I]]
[[Category: Williams DL]]