7ros: Difference between revisions
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==Plasmodium falciparum tyrosyl-tRNA synthetase in complex with ML901-Tyr== | ==Plasmodium falciparum tyrosyl-tRNA synthetase in complex with ML901-Tyr== | ||
<StructureSection load='7ros' size='340' side='right'caption='[[7ros]]' scene=''> | <StructureSection load='7ros' size='340' side='right'caption='[[7ros]], [[Resolution|resolution]] 2.15Å' 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=7ROS OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7ROS FirstGlance]. <br> | <table><tr><td colspan='2'>[[7ros]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7ROS OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7ROS 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=7ros FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7ros OCA], [https://pdbe.org/7ros PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7ros RCSB], [https://www.ebi.ac.uk/pdbsum/7ros PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7ros ProSAT]</span></td></tr> | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=66I:{(2R,3S,4R,5R)-5-[4-amino-3-(difluoromethoxy)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-3,4-dihydroxyoxolan-2-yl}methyl+[(2S)-2-amino-3-(4-hydroxyphenyl)propanoyl]sulfamate+(non-preferred+name)'>66I</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene></td></tr> | ||
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Tyrosine--tRNA_ligase Tyrosine--tRNA ligase], with EC number [https://www.brenda-enzymes.info/php/result_flat.php4?ecno=6.1.1.1 6.1.1.1] </span></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=7ros FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7ros OCA], [https://pdbe.org/7ros PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7ros RCSB], [https://www.ebi.ac.uk/pdbsum/7ros PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7ros ProSAT]</span></td></tr> | |||
</table> | </table> | ||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Aminoacyl transfer RNA (tRNA) synthetases (aaRSs) are attractive drug targets, and we present class I and II aaRSs as previously unrecognized targets for adenosine 5'-monophosphate-mimicking nucleoside sulfamates. The target enzyme catalyzes the formation of an inhibitory amino acid-sulfamate conjugate through a reaction-hijacking mechanism. We identified adenosine 5'-sulfamate as a broad-specificity compound that hijacks a range of aaRSs and ML901 as a specific reagent a specific reagent that hijacks a single aaRS in the malaria parasite Plasmodium falciparum, namely tyrosine RS (PfYRS). ML901 exerts whole-life-cycle-killing activity with low nanomolar potency and single-dose efficacy in a mouse model of malaria. X-ray crystallographic studies of plasmodium and human YRSs reveal differential flexibility of a loop over the catalytic site that underpins differential susceptibility to reaction hijacking by ML901. | |||
Reaction hijacking of tyrosine tRNA synthetase as a new whole-of-life-cycle antimalarial strategy.,Xie SC, Metcalfe RD, Dunn E, Morton CJ, Huang SC, Puhalovich T, Du Y, Wittlin S, Nie S, Luth MR, Ma L, Kim MS, Pasaje CFA, Kumpornsin K, Giannangelo C, Houghton FJ, Churchyard A, Famodimu MT, Barry DC, Gillett DL, Dey S, Kosasih CC, Newman W, Niles JC, Lee MCS, Baum J, Ottilie S, Winzeler EA, Creek DJ, Williamson N, Parker MW, Brand S, Langston SP, Dick LR, Griffin MDW, Gould AE, Tilley L Science. 2022 Jun 3;376(6597):1074-1079. doi: 10.1126/science.abn0611. Epub 2022 , Jun 2. PMID:35653481<ref>PMID:35653481</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 7ros" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Griffin | [[Category: Tyrosine--tRNA ligase]] | ||
[[Category: Metcalfe | [[Category: Griffin, M D.W]] | ||
[[Category: Morton | [[Category: Metcalfe, R D]] | ||
[[Category: Tilley L]] | [[Category: Morton, C J]] | ||
[[Category: Xie | [[Category: Tilley, L]] | ||
[[Category: Xie, S C]] | |||
[[Category: Enzyme]] | |||
[[Category: Inhibitor]] | |||
[[Category: Ligase]] | |||
[[Category: Malaria]] | |||
[[Category: Tyrosine-amp]] | |||
[[Category: Tyrosyl-trna synthetase]] | |||
Revision as of 10:33, 29 June 2022
Plasmodium falciparum tyrosyl-tRNA synthetase in complex with ML901-TyrPlasmodium falciparum tyrosyl-tRNA synthetase in complex with ML901-Tyr
Structural highlights
Publication Abstract from PubMedAminoacyl transfer RNA (tRNA) synthetases (aaRSs) are attractive drug targets, and we present class I and II aaRSs as previously unrecognized targets for adenosine 5'-monophosphate-mimicking nucleoside sulfamates. The target enzyme catalyzes the formation of an inhibitory amino acid-sulfamate conjugate through a reaction-hijacking mechanism. We identified adenosine 5'-sulfamate as a broad-specificity compound that hijacks a range of aaRSs and ML901 as a specific reagent a specific reagent that hijacks a single aaRS in the malaria parasite Plasmodium falciparum, namely tyrosine RS (PfYRS). ML901 exerts whole-life-cycle-killing activity with low nanomolar potency and single-dose efficacy in a mouse model of malaria. X-ray crystallographic studies of plasmodium and human YRSs reveal differential flexibility of a loop over the catalytic site that underpins differential susceptibility to reaction hijacking by ML901. Reaction hijacking of tyrosine tRNA synthetase as a new whole-of-life-cycle antimalarial strategy.,Xie SC, Metcalfe RD, Dunn E, Morton CJ, Huang SC, Puhalovich T, Du Y, Wittlin S, Nie S, Luth MR, Ma L, Kim MS, Pasaje CFA, Kumpornsin K, Giannangelo C, Houghton FJ, Churchyard A, Famodimu MT, Barry DC, Gillett DL, Dey S, Kosasih CC, Newman W, Niles JC, Lee MCS, Baum J, Ottilie S, Winzeler EA, Creek DJ, Williamson N, Parker MW, Brand S, Langston SP, Dick LR, Griffin MDW, Gould AE, Tilley L Science. 2022 Jun 3;376(6597):1074-1079. doi: 10.1126/science.abn0611. Epub 2022 , Jun 2. PMID:35653481[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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