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==Crystal structure of threonyl-tRNA synthetase (ThrRS) from Salmonella enterica in complex with an inhibitor== | |||
<StructureSection load='7cbg' size='340' side='right'caption='[[7cbg]], [[Resolution|resolution]] 2.50Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[7cbg]] 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=7CBG OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7CBG 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]] 2.5Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=FQL:(2S,3R)-N-[(E)-4-[6,7-bis(chloranyl)-4-oxidanylidene-quinazolin-3-yl]but-2-enyl]-2-(methylamino)-3-oxidanyl-butanamide'>FQL</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=7cbg FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7cbg OCA], [https://pdbe.org/7cbg PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7cbg RCSB], [https://www.ebi.ac.uk/pdbsum/7cbg PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7cbg 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 an attractive class of antibacterial drug targets due to their essential roles in protein translation. While most traditional aaRS inhibitors target the binding pockets of substrate amino acids and/or ATP, we recently developed a class of novel tRNA-amino acid dual-site inhibitors including inhibitor 3 ((2S,3R)-2-amino-N-((E)-4-(6,7-dichloro-4-oxoquinazolin-3(4H)-yl)but-2-en-1-yl)-3 -hydroxybutanamide) against threonyl-tRNA synthetase (ThrRS). Here, the binding modes and structure-activity relationships (SARs) of these inhibitors were analyzed by the crystal structures of Salmonella enterica ThrRS (SeThrRS) in complex with three of them. Based on the cocrystal structures, twelve quinazolinone-threonine hybrids were designed and synthesized, and their affinities, enzymatic inhibitory activities, and cellular potencies were evaluated. The best derivative 8g achieved a Kd value of 0.40 muM, an IC50 value of 0.50 muM against SeThrRS and MIC values of 16-32 mug/mL against the tested bacterial strains. The cocrystal structure of the SeThrRS-8g complex revealed that 8g induced a bended conformation for Met332 by forming hydrophobic interactions, which better mimicked the binding of tRNA(Thr) to ThrRS. Moreover, the inhibitory potency of 8g was less impaired than a reported ATP competitive inhibitor at high concentrations of ATP, supporting our hypothesis that tRNA site inhibitors are likely superior to ATP site inhibitors in vivo, where ATP typically reaches millimolar concentrations. | |||
Structure-guided optimization and mechanistic study of a class of quinazolinone-threonine hybrids as antibacterial ThrRS inhibitors.,Guo J, Chen B, Yu Y, Cheng B, Ju Y, Tang J, Cai Z, Gu Q, Xu J, Zhou H Eur J Med Chem. 2020 Sep 19;207:112848. doi: 10.1016/j.ejmech.2020.112848. PMID:32980741<ref>PMID:32980741</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
[[Category: | <div class="pdbe-citations 7cbg" style="background-color:#fffaf0;"></div> | ||
[[Category: Guo | |||
[[Category: | ==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: Chen B]] | |||
[[Category: Guo J]] | |||
[[Category: Zhou H]] | |||
Latest revision as of 19:02, 29 November 2023
Crystal structure of threonyl-tRNA synthetase (ThrRS) from Salmonella enterica in complex with an inhibitorCrystal structure of threonyl-tRNA synthetase (ThrRS) from Salmonella enterica in complex with an inhibitor
Structural highlights
FunctionPublication Abstract from PubMedAminoacyl-tRNA synthetases (aaRSs) are an attractive class of antibacterial drug targets due to their essential roles in protein translation. While most traditional aaRS inhibitors target the binding pockets of substrate amino acids and/or ATP, we recently developed a class of novel tRNA-amino acid dual-site inhibitors including inhibitor 3 ((2S,3R)-2-amino-N-((E)-4-(6,7-dichloro-4-oxoquinazolin-3(4H)-yl)but-2-en-1-yl)-3 -hydroxybutanamide) against threonyl-tRNA synthetase (ThrRS). Here, the binding modes and structure-activity relationships (SARs) of these inhibitors were analyzed by the crystal structures of Salmonella enterica ThrRS (SeThrRS) in complex with three of them. Based on the cocrystal structures, twelve quinazolinone-threonine hybrids were designed and synthesized, and their affinities, enzymatic inhibitory activities, and cellular potencies were evaluated. The best derivative 8g achieved a Kd value of 0.40 muM, an IC50 value of 0.50 muM against SeThrRS and MIC values of 16-32 mug/mL against the tested bacterial strains. The cocrystal structure of the SeThrRS-8g complex revealed that 8g induced a bended conformation for Met332 by forming hydrophobic interactions, which better mimicked the binding of tRNA(Thr) to ThrRS. Moreover, the inhibitory potency of 8g was less impaired than a reported ATP competitive inhibitor at high concentrations of ATP, supporting our hypothesis that tRNA site inhibitors are likely superior to ATP site inhibitors in vivo, where ATP typically reaches millimolar concentrations. Structure-guided optimization and mechanistic study of a class of quinazolinone-threonine hybrids as antibacterial ThrRS inhibitors.,Guo J, Chen B, Yu Y, Cheng B, Ju Y, Tang J, Cai Z, Gu Q, Xu J, Zhou H Eur J Med Chem. 2020 Sep 19;207:112848. doi: 10.1016/j.ejmech.2020.112848. PMID:32980741[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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