5xii: Difference between revisions
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<StructureSection load='5xii' size='340' side='right'caption='[[5xii]], [[Resolution|resolution]] 2.17Å' scene=''> | <StructureSection load='5xii' size='340' side='right'caption='[[5xii]], [[Resolution|resolution]] 2.17Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[5xii]] is a 4 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5XII OCA]. For a <b>guided tour on the structure components</b> use [ | <table><tr><td colspan='2'>[[5xii]] 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=5XII OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5XII FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=86X:6-chloranyl-7-fluoranyl-3-[3-[(2R)-3-oxidanylidenepiperidin-2-yl]propyl]quinazolin-4-one'>86X</scene>, <scene name='pdbligand=ANP:PHOSPHOAMINOPHOSPHONIC+ACID-ADENYLATE+ESTER'>ANP</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.17Å</td></tr> | ||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=86X:6-chloranyl-7-fluoranyl-3-[3-[(2R)-3-oxidanylidenepiperidin-2-yl]propyl]quinazolin-4-one'>86X</scene>, <scene name='pdbligand=ANP:PHOSPHOAMINOPHOSPHONIC+ACID-ADENYLATE+ESTER'>ANP</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</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=5xii FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5xii OCA], [https://pdbe.org/5xii PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5xii RCSB], [https://www.ebi.ac.uk/pdbsum/5xii PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5xii ProSAT]</span></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[ | |||
</table> | </table> | ||
== Function == | |||
[https://www.uniprot.org/uniprot/S8G8I1_TOXGM S8G8I1_TOXGM] | |||
<div style="background-color:#fffaf0;"> | <div style="background-color:#fffaf0;"> | ||
== Publication Abstract from PubMed == | == Publication Abstract from PubMed == | ||
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</StructureSection> | </StructureSection> | ||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: | [[Category: Toxoplasma gondii ME49]] | ||
[[Category: Jain | [[Category: Jain V]] | ||
[[Category: Manickam | [[Category: Manickam Y]] | ||
[[Category: Sharma | [[Category: Sharma A]] | ||
Latest revision as of 11:03, 22 November 2023
Crystal Structure of Toxoplasma gondii Prolyl-tRNA Synthetase (TgPRS) in complex with inhibitor 6Crystal Structure of Toxoplasma gondii Prolyl-tRNA Synthetase (TgPRS) in complex with inhibitor 6
Structural highlights
FunctionPublication Abstract from PubMedDeveloping anti-parasitic lead compounds that act on key vulnerabilities are necessary for new anti-infectives. Malaria, leishmaniasis, toxoplasmosis, cryptosporidiosis and coccidiosis together kill >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[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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