View source for 6zp3


==Thioredoxin glutathione reductase from Schistosoma mansoni in complex with 2-Methylindole-3-acetic acid==
<StructureSection load='6zp3' size='340' side='right'caption='[[6zp3]], [[Resolution|resolution]] 1.80&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6ZP3 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6ZP3 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=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=DTT:2,3-DIHYDROXY-1,4-DITHIOBUTANE'>DTT</scene>, <scene name='pdbligand=FAD:FLAVIN-ADENINE+DINUCLEOTIDE'>FAD</scene>, <scene name='pdbligand=K:POTASSIUM+ION'>K</scene>, <scene name='pdbligand=PEG:DI(HYDROXYETHYL)ETHER'>PEG</scene>, <scene name='pdbligand=PG4:TETRAETHYLENE+GLYCOL'>PG4</scene>, <scene name='pdbligand=PGE:TRIETHYLENE+GLYCOL'>PGE</scene>, <scene name='pdbligand=QN5:2-(2-methyl-1~{H}-indol-3-yl)ethanoic+acid'>QN5</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=6zp3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6zp3 OCA], [https://pdbe.org/6zp3 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6zp3 RCSB], [https://www.ebi.ac.uk/pdbsum/6zp3 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6zp3 ProSAT]</span></td></tr>
</table>
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== Publication Abstract from PubMed ==
Fragment screening is a powerful drug discovery approach particularly useful for enzymes difficult to inhibit selectively, such as the thiol/selenol-dependent thioredoxin reductases (TrxRs), which are essential and druggable in several infectious diseases. Several known inhibitors are reactive electrophiles targeting the selenocysteine-containing C-terminus and thus often suffering from off-target reactivity in vivo. The lack of structural information on the interaction modalities of the C-terminus-targeting inhibitors, due to the high mobility of this domain and the lack of alternative druggable sites, prevents the development of selective inhibitors for TrxRs. In this work, fragments selected from actives identified in a large screen carried out against Thioredoxin Glutathione Reductase from Schistosoma mansoni (SmTGR) were probed by X-ray crystallography. SmTGR is one of the most promising drug targets for schistosomiasis, a devastating, neglected disease. Utilizing a multicrystal method to analyze electron density maps, structural analysis, and functional studies, three binding sites were characterized in SmTGR: two sites are close to or partially superposable with the NADPH binding site, while the third one is found between two symmetry related SmTGR subunits of the crystal lattice. Surprisingly, one compound bound to this latter site stabilizes, through allosteric effects mediated by the so-called guiding bar residues, the crucial redox active C-terminus of SmTGR, making it finally visible at high resolution. These results further promote fragments as small molecule probes for investigating functional aspects of the target protein, exemplified by the allosteric effect on the C-terminus, and providing fundamental chemical information exploitable in drug discovery.

Probing the Surface of a Parasite Drug Target Thioredoxin Glutathione Reductase Using Small Molecule Fragments.,Fata F, Silvestri I, Ardini M, Ippoliti R, Di Leandro L, Demitri N, Polentarutti M, Di Matteo A, Lyu H, Thatcher GRJ, Petukhov PA, Williams DL, Angelucci F ACS Infect Dis. 2021 May 5. doi: 10.1021/acsinfecdis.0c00909. PMID:33950676<ref>PMID:33950676</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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<div class="pdbe-citations 6zp3" style="background-color:#fffaf0;"></div>

==See Also==
*[[Thioredoxin Glutathione Reductase|Thioredoxin Glutathione Reductase]]
== References ==
<references/>
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</StructureSection>
[[Category: Large Structures]]
[[Category: Angelucci F]]
[[Category: Fata F]]
[[Category: Silvestri I]]
[[Category: Williams DL]]