View source for 5xih


==Crystal Structure of Toxoplasma gondii Prolyl-tRNA Synthetase (TgPRS) in complex with inhibitor 5==
<StructureSection load='5xih' size='340' side='right'caption='[[5xih]], [[Resolution|resolution]] 2.20&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[5xih]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Toxoplasma_gondii_ME49 Toxoplasma gondii ME49]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5XIH OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5XIH 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]] 2.2&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=86U:6,7-bis(fluoranyl)-3-[3-[(2R)-3-oxidanylidenepiperidin-2-yl]propyl]quinazolin-4-one'>86U</scene>, <scene name='pdbligand=ANP:PHOSPHOAMINOPHOSPHONIC+ACID-ADENYLATE+ESTER'>ANP</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</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=5xih FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5xih OCA], [https://pdbe.org/5xih PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5xih RCSB], [https://www.ebi.ac.uk/pdbsum/5xih PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5xih ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/S8G8I1_TOXGM S8G8I1_TOXGM] 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Developing anti-parasitic lead compounds that act on key vulnerabilities are necessary for new anti-infectives. Malaria, leishmaniasis, toxoplasmosis, cryptosporidiosis and coccidiosis together kill &gt;500,000 humans annually. Their causative parasites Plasmodium, Leishmania, Toxoplasma, Cryptosporidium and Eimeria display high conservation in many housekeeping genes, suggesting that these parasites can be attacked by targeting invariant essential proteins. Here, we describe selective and potent inhibition of prolyl-tRNA synthetases (PRSs) from the above parasites using a series of quinazolinone-scaffold compounds. Our PRS-drug co-crystal structures reveal remarkable active site plasticity that accommodates diversely substituted compounds, an enzymatic feature that can be leveraged for refining drug-like properties of quinazolinones on a per parasite basis. A compound we termed In-5 exhibited a unique double conformation, enhanced drug-like properties, and cleared malaria in mice. It thus represents a new lead for optimization. Collectively, our data offer insights into the structure-guided optimization of quinazolinone-based compounds for drug development against multiple human eukaryotic pathogens.

Targeting Prolyl-tRNA Synthetase to Accelerate Drug Discovery against Malaria, Leishmaniasis, Toxoplasmosis, Cryptosporidiosis, and Coccidiosis.,Jain V, Yogavel M, Kikuchi H, Oshima Y, Hariguchi N, Matsumoto M, Goel P, Touquet B, Jumani RS, Tacchini-Cottier F, Harlos K, Huston CD, Hakimi MA, Sharma A Structure. 2017 Oct 3;25(10):1495-1505.e6. doi: 10.1016/j.str.2017.07.015. Epub, 2017 Aug 31. PMID:28867614<ref>PMID:28867614</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 5xih" style="background-color:#fffaf0;"></div>

==See Also==
*[[Aminoacyl tRNA synthetase 3D structures|Aminoacyl tRNA synthetase 3D structures]]
== References ==
<references/>
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</StructureSection>
[[Category: Large Structures]]
[[Category: Toxoplasma gondii ME49]]
[[Category: Jain V]]
[[Category: Manickam Y]]
[[Category: Sharma A]]