7ap3: Difference between revisions
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==Crystal structure of E. coli tyrosyl-tRNA synthetase in complex with TyrS7HMDDA== | |||
<StructureSection load='7ap3' size='340' side='right'caption='[[7ap3]], [[Resolution|resolution]] 2.00Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[7ap3]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Escherichia_coli_BL21(DE3) Escherichia coli BL21(DE3)]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7AP3 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7AP3 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]] 2Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=RRB:[(2~{R},3~{S},4~{R},5~{R})-5-[7-azanyl-5-(hydroxymethyl)benzimidazol-1-yl]-3,4-bis(oxidanyl)oxolan-2-yl]methyl+~{N}-[(2~{S})-2-azanyl-3-(4-hydroxyphenyl)propanoyl]sulfamate'>RRB</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=7ap3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7ap3 OCA], [https://pdbe.org/7ap3 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7ap3 RCSB], [https://www.ebi.ac.uk/pdbsum/7ap3 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7ap3 ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/SYY_ECOLI SYY_ECOLI] Catalyzes the attachment of tyrosine to tRNA(Tyr) in a two-step reaction: tyrosine is first activated by ATP to form Tyr-AMP and then transferred to the acceptor end of tRNA(Tyr).[HAMAP-Rule:MF_02006] | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Aminoacyl-tRNA synthetases (aaRSs) have become viable targets for the development of antimicrobial agents due to their crucial role in protein translation. A series of six amino acids were coupled to the purine-like 7-amino-5-hydroxymethylbenzimidazole nucleoside analogue following an optimized synthetic pathway. These compounds were designed as aaRS inhibitors and can be considered as 1,3-dideazaadenine analogues carrying a 2-hydroxymethyl substituent. Despite our intentions to obtain N(1)-glycosylated 4-aminobenzimidazole congeners, resembling the natural purine nucleosides glycosylated at the N(9)-position, we obtained the N(3)-glycosylated benzimidazole derivatives as the major products, resembling the respective purine N(7)-glycosylated nucleosides. A series of X-ray crystal structures of class I and II aaRSs in complex with newly synthesized compounds revealed interesting interactions of these "base-flipped" analogues with their targets. While the exocyclic amine of the flipped base mimics the reciprocal interaction of the N(3)-purine atom of aminoacyl-sulfamoyl adenosine (aaSA) congeners, the hydroxymethyl substituent of the flipped base apparently loses part of the standard interactions of the adenine N(1) and the N(6)-amine as seen with aaSA analogues. Upon the evaluation of the inhibitory potency of the newly obtained analogues, nanomolar inhibitory activities were noted for the leucine and isoleucine analogues targeting class I aaRS enzymes, while rather weak inhibitory activity against the corresponding class II aaRSs was observed. This class bias could be further explained by detailed structural analysis. | |||
Synthesis and Biological Evaluation of 1,3-Dideazapurine-Like 7-Amino-5-Hydroxymethyl-Benzimidazole Ribonucleoside Analogues as Aminoacyl-tRNA Synthetase Inhibitors.,Zhang B, Pang L, Nautiyal M, De Graef S, Gadakh B, Lescrinier E, Rozenski J, Strelkov SV, Weeks SD, Van Aerschot A Molecules. 2020 Oct 16;25(20). pii: molecules25204751. doi:, 10.3390/molecules25204751. PMID:33081246<ref>PMID:33081246</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
[[Category: | <div class="pdbe-citations 7ap3" style="background-color:#fffaf0;"></div> | ||
[[Category: | |||
[[Category: Strelkov | ==See Also== | ||
[[Category: | *[[Aminoacyl tRNA synthetase 3D structures|Aminoacyl tRNA synthetase 3D structures]] | ||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Large Structures]] | |||
[[Category: De Graef S]] | |||
[[Category: Pang L]] | |||
[[Category: Strelkov SV]] | |||
[[Category: Weeks SD]] | |||
Latest revision as of 15:13, 1 February 2024
Crystal structure of E. coli tyrosyl-tRNA synthetase in complex with TyrS7HMDDACrystal structure of E. coli tyrosyl-tRNA synthetase in complex with TyrS7HMDDA
Structural highlights
FunctionSYY_ECOLI Catalyzes the attachment of tyrosine to tRNA(Tyr) in a two-step reaction: tyrosine is first activated by ATP to form Tyr-AMP and then transferred to the acceptor end of tRNA(Tyr).[HAMAP-Rule:MF_02006] Publication Abstract from PubMedAminoacyl-tRNA synthetases (aaRSs) have become viable targets for the development of antimicrobial agents due to their crucial role in protein translation. A series of six amino acids were coupled to the purine-like 7-amino-5-hydroxymethylbenzimidazole nucleoside analogue following an optimized synthetic pathway. These compounds were designed as aaRS inhibitors and can be considered as 1,3-dideazaadenine analogues carrying a 2-hydroxymethyl substituent. Despite our intentions to obtain N(1)-glycosylated 4-aminobenzimidazole congeners, resembling the natural purine nucleosides glycosylated at the N(9)-position, we obtained the N(3)-glycosylated benzimidazole derivatives as the major products, resembling the respective purine N(7)-glycosylated nucleosides. A series of X-ray crystal structures of class I and II aaRSs in complex with newly synthesized compounds revealed interesting interactions of these "base-flipped" analogues with their targets. While the exocyclic amine of the flipped base mimics the reciprocal interaction of the N(3)-purine atom of aminoacyl-sulfamoyl adenosine (aaSA) congeners, the hydroxymethyl substituent of the flipped base apparently loses part of the standard interactions of the adenine N(1) and the N(6)-amine as seen with aaSA analogues. Upon the evaluation of the inhibitory potency of the newly obtained analogues, nanomolar inhibitory activities were noted for the leucine and isoleucine analogues targeting class I aaRS enzymes, while rather weak inhibitory activity against the corresponding class II aaRSs was observed. This class bias could be further explained by detailed structural analysis. Synthesis and Biological Evaluation of 1,3-Dideazapurine-Like 7-Amino-5-Hydroxymethyl-Benzimidazole Ribonucleoside Analogues as Aminoacyl-tRNA Synthetase Inhibitors.,Zhang B, Pang L, Nautiyal M, De Graef S, Gadakh B, Lescrinier E, Rozenski J, Strelkov SV, Weeks SD, Van Aerschot A Molecules. 2020 Oct 16;25(20). pii: molecules25204751. doi:, 10.3390/molecules25204751. PMID:33081246[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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