View source for 7evu


==Co-crystal Structure of Toxoplasma gondii Prolyl tRNA Synthetase (TgPRS) in complex with HFG and JE6==
<StructureSection load='7evu' size='340' side='right'caption='[[7evu]], [[Resolution|resolution]] 1.70&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[7evu]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Toxoplasma_gondii Toxoplasma gondii]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7EVU OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7EVU 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]] 1.697&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=HFG:7-BROMO-6-CHLORO-3-{3-[(2R,3S)-3-HYDROXYPIPERIDIN-2-YL]-2-OXOPROPYL}QUINAZOLIN-4(3H)-ONE'>HFG</scene>, <scene name='pdbligand=JE6:~{N}-[4-[(3~{S})-3-cyano-3-cyclopropyl-2-oxidanylidene-pyrrolidin-1-yl]-6-methyl-pyridin-2-yl]-2-phenyl-ethanamide'>JE6</scene>, <scene name='pdbligand=MES:2-(N-MORPHOLINO)-ETHANESULFONIC+ACID'>MES</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=7evu FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7evu OCA], [https://pdbe.org/7evu PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7evu RCSB], [https://www.ebi.ac.uk/pdbsum/7evu PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7evu ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/A0A7J6JUK2_TOXGO A0A7J6JUK2_TOXGO] 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Toxoplasmosis is caused by Toxoplasma gondii and in immunocompromised patients it may lead to seizures, encephalitis or death. The conserved enzyme prolyl-tRNA synthetase (PRS) is a validated druggable target in Toxoplasma gondii but the traditional 'single target-single drug' approach has its caveats. Here, we describe two potent inhibitors namely halofuginone (HFG) and a novel ATP mimetic (L95) that bind to Toxoplasma gondii PRS simultaneously at different neighbouring sites to cover all three of the enzyme substrate subsites. HFG and L95 act as one triple-site inhibitor in tandem and form an unusual ternary complex wherein HFG occupies the 3'-end of tRNA and the L-proline (L-pro) binding sites while L95 occupies the ATP pocket. These inhibitors exhibit nanomolar IC50 and EC50 values independently, and when given together reveal an additive mode of action in parasite inhibition assays. This work validates a novel approach and lays a structural framework for further drug development based on simultaneous targeting of multiple pockets to inhibit druggable proteins.

Double drugging of prolyl-tRNA synthetase provides a new paradigm for anti-infective drug development.,Manickam Y, Malhotra N, Mishra S, Babbar P, Dusane A, Laleu B, Bellini V, Hakimi MA, Bougdour A, Sharma A PLoS Pathog. 2022 Mar 25;18(3):e1010363. doi: 10.1371/journal.ppat.1010363., eCollection 2022 Mar. PMID:35333915<ref>PMID:35333915</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 7evu" 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: Toxoplasma gondii]]
[[Category: Malhotra N]]
[[Category: Manickam Y]]
[[Category: Mishra S]]
[[Category: Sharma A]]