View source for 7wmi


==Threonyl-tRNA synthetase from Salmonella enterica in complex with an inhibitor==
<StructureSection load='7wmi' size='340' side='right'caption='[[7wmi]], [[Resolution|resolution]] 2.00&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[7wmi]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Salmonella_enterica_subsp._enterica_serovar_Cubana_str._76814 Salmonella enterica subsp. enterica serovar Cubana str. 76814]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7WMI OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7WMI 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&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=9IC:(2S,3R)-2-azanyl-N-[(1R)-2-[3-(7-bromanyl-6-chloranyl-4-oxidanylidene-quinazolin-3-yl)propanoylamino]-1-(3-phenylphenyl)ethyl]-3-oxidanyl-butanamide'>9IC</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</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=7wmi FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7wmi OCA], [https://pdbe.org/7wmi PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7wmi RCSB], [https://www.ebi.ac.uk/pdbsum/7wmi PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7wmi ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/V7II86_SALET V7II86_SALET] 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Aminoacyl-tRNA synthetases (aaRSs) are promising drug targets due to their essential roles in protein translation. Although current inhibitors primarily occupy one or two of the three substrate binding sites on aaRSs, we report here the structure-based design of the first class of triple-site aaRS inhibitors by targeting Salmonella enterica threonyl-tRNA synthetase (SeThrRS). Competition of our compounds with all three substrates on SeThrRS binding was confirmed via isothermal titration calorimetry assays. Cocrystal structures of three compounds bound to SeThrRS unambiguously confirmed their substrate-mimicking triple-site binding mode. Compound 36j exhibited the best enzyme activity against SeThrRS with IC50 = 19 nM and Kd = 35.4 nM. Compounds 36b, 36k, and 36l exhibited antibacterial activities with minimum inhibitory concentration values of 2-8 mug/mL against the tested bacteria, which are superior to those of the reported dual-site ThrRS inhibitors. Our study provides the first proof-of-concept for developing triple-site inhibitors against aaRSs, inspiring future aaRS-based drug discoveries.

Design, Synthesis, and Proof-of-Concept of Triple-Site Inhibitors against Aminoacyl-tRNA Synthetases.,Cai Z, Chen B, Yu Y, Guo J, Luo Z, Cheng B, Xu J, Gu Q, Zhou H J Med Chem. 2022 Apr 14;65(7):5800-5820. doi: 10.1021/acs.jmedchem.2c00134. Epub , 2022 Apr 1. PMID:35363470<ref>PMID:35363470</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 7wmi" style="background-color:#fffaf0;"></div>

==See Also==
*[[Aminoacyl tRNA synthetase 3D structures|Aminoacyl tRNA synthetase 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Large Structures]]
[[Category: Salmonella enterica subsp. enterica serovar Cubana str. 76814]]
[[Category: Cai Z]]
[[Category: Chen B]]
[[Category: Yu Y]]
[[Category: Zhou H]]