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==Co-crystal Structure of Toxoplasma gondii Prolyl tRNA Synthetase (TgPRS) in complex with JE6 and L-pro== | ==Co-crystal Structure of Toxoplasma gondii Prolyl tRNA Synthetase (TgPRS) in complex with JE6 and L-pro== | ||
<StructureSection load='7evv' size='340' side='right'caption='[[7evv]]' scene=''> | <StructureSection load='7evv' size='340' side='right'caption='[[7evv]], [[Resolution|resolution]] 1.70Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7EVV OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7EVV FirstGlance]. <br> | <table><tr><td colspan='2'>[[7evv]] is a 1 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=7EVV OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7EVV FirstGlance]. <br> | ||
</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=7evv FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7evv OCA], [https://pdbe.org/7evv PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7evv RCSB], [https://www.ebi.ac.uk/pdbsum/7evv PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7evv ProSAT]</span></td></tr> | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.704Å</td></tr> | ||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</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=MPD:(4S)-2-METHYL-2,4-PENTANEDIOL'>MPD</scene>, <scene name='pdbligand=PRO:PROLINE'>PRO</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=7evv FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7evv OCA], [https://pdbe.org/7evv PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7evv RCSB], [https://www.ebi.ac.uk/pdbsum/7evv PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7evv ProSAT]</span></td></tr> | |||
</table> | </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®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 7evv" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[Aminoacyl tRNA synthetase 3D structures|Aminoacyl tRNA synthetase 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Toxoplasma gondii]] | |||
[[Category: Malhotra N]] | [[Category: Malhotra N]] | ||
[[Category: Manickam Y]] | [[Category: Manickam Y]] | ||
[[Category: Mishra S]] | [[Category: Mishra S]] | ||
[[Category: Sharma A]] | [[Category: Sharma A]] | ||
Latest revision as of 20:05, 29 November 2023
Co-crystal Structure of Toxoplasma gondii Prolyl tRNA Synthetase (TgPRS) in complex with JE6 and L-proCo-crystal Structure of Toxoplasma gondii Prolyl tRNA Synthetase (TgPRS) in complex with JE6 and L-pro
Structural highlights
FunctionPublication Abstract from PubMedToxoplasmosis 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[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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