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==Crystal Structure of a human cytosolic histidyl-tRNA synthetase, histidine-bound== | ==Crystal Structure of a human cytosolic histidyl-tRNA synthetase, histidine-bound== | ||
<StructureSection load='4phc' size='340' side='right' caption='[[4phc]], [[Resolution|resolution]] 2.84Å' scene=''> | <StructureSection load='4phc' size='340' side='right'caption='[[4phc]], [[Resolution|resolution]] 2.84Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[4phc]] is a 4 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4PHC OCA]. For a <b>guided tour on the structure components</b> use [ | <table><tr><td colspan='2'>[[4phc]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4PHC OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4PHC FirstGlance]. <br> | ||
</td></tr><tr id=' | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.844Å</td></tr> | ||
<tr id=' | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=HIS:HISTIDINE'>HIS</scene></td></tr> | ||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[ | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4phc FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4phc OCA], [https://pdbe.org/4phc PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4phc RCSB], [https://www.ebi.ac.uk/pdbsum/4phc PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4phc ProSAT]</span></td></tr> | ||
</table> | </table> | ||
== Disease == | == Disease == | ||
[ | [https://www.uniprot.org/uniprot/HARS1_HUMAN HARS1_HUMAN] Usher syndrome type 3;Autosomal dominant Charcot-Marie-Tooth disease type 2W. The disease is caused by variants affecting the gene represented in this entry. The disease is caused by variants affecting the gene represented in this entry. | ||
== Function == | |||
[https://www.uniprot.org/uniprot/HARS1_HUMAN HARS1_HUMAN] Catalyzes the ATP-dependent ligation of histidine to the 3'-end of its cognate tRNA, via the formation of an aminoacyl-adenylate intermediate (His-AMP) (PubMed:29235198). Plays a role in axon guidance (PubMed:26072516).<ref>PMID:26072516</ref> <ref>PMID:29235198</ref> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
As part of a project aimed at obtaining selective inhibitors and drug-like compounds targeting tRNA synthetases from trypanosomatids, we have elucidated the crystal structure of human cytosolic histidyl-tRNA synthetase (Hs-cHisRS) in complex with histidine in order to be able to compare human and parasite enzymes. The resultant structure of Hs-cHisRS*His represents the substrate-bound state (H-state) of the enzyme. It provides an interesting opportunity to compare with ligand-free and imidazole-bound structures Hs-cHisRS published recently, both of which represent the ligand-free state (F-state) of the enzyme. The H-state Hs-cHisRS undergoes conformational changes in active site residues and several conserved motif of HisRS, compared to F-state structures. The histidine forms eight hydrogen bonds with HisRS of which six engage the amino and carboxylate groups of this amino acid. The availability of published imidazole-bound structure provides a unique opportunity to dissect the structural roles of individual chemical groups of histidine. The analysis revealed the importance of the amino and carboxylate groups, of the histidine in leading to these dramatic conformational changes of the H-state. Further, comparison with previously published trypanosomatid HisRS structures reveals a pocket in the F-state of the parasite enzyme that may provide opportunities for developing specific inhibitors of Trypanosoma brucei HisRS. | |||
Comparison of histidine recognition in human and trypanosomatid histidyl-tRNA synthetases.,Koh CY, Wetzel AB, de van der Schueren WJ, Hol WG Biochimie. 2014 Nov;106:111-20. doi: 10.1016/j.biochi.2014.08.005. Epub 2014 Aug , 20. PMID:25151410<ref>PMID:25151410</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 4phc" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[Aminoacyl tRNA synthetase 3D structures|Aminoacyl tRNA synthetase 3D structures]] | |||
== References == | == References == | ||
<references/> | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: | [[Category: Homo sapiens]] | ||
[[Category: | [[Category: Large Structures]] | ||
[[Category: | [[Category: Hol WGJ]] | ||
[[Category: | [[Category: Koh CY]] | ||
[[Category: Wetzel | [[Category: Wetzel AB]] | ||
[[Category: | [[Category: De van der Schueren WJ]] | ||
Latest revision as of 03:43, 28 December 2023
Crystal Structure of a human cytosolic histidyl-tRNA synthetase, histidine-boundCrystal Structure of a human cytosolic histidyl-tRNA synthetase, histidine-bound
Structural highlights
DiseaseHARS1_HUMAN Usher syndrome type 3;Autosomal dominant Charcot-Marie-Tooth disease type 2W. The disease is caused by variants affecting the gene represented in this entry. The disease is caused by variants affecting the gene represented in this entry. FunctionHARS1_HUMAN Catalyzes the ATP-dependent ligation of histidine to the 3'-end of its cognate tRNA, via the formation of an aminoacyl-adenylate intermediate (His-AMP) (PubMed:29235198). Plays a role in axon guidance (PubMed:26072516).[1] [2] Publication Abstract from PubMedAs part of a project aimed at obtaining selective inhibitors and drug-like compounds targeting tRNA synthetases from trypanosomatids, we have elucidated the crystal structure of human cytosolic histidyl-tRNA synthetase (Hs-cHisRS) in complex with histidine in order to be able to compare human and parasite enzymes. The resultant structure of Hs-cHisRS*His represents the substrate-bound state (H-state) of the enzyme. It provides an interesting opportunity to compare with ligand-free and imidazole-bound structures Hs-cHisRS published recently, both of which represent the ligand-free state (F-state) of the enzyme. The H-state Hs-cHisRS undergoes conformational changes in active site residues and several conserved motif of HisRS, compared to F-state structures. The histidine forms eight hydrogen bonds with HisRS of which six engage the amino and carboxylate groups of this amino acid. The availability of published imidazole-bound structure provides a unique opportunity to dissect the structural roles of individual chemical groups of histidine. The analysis revealed the importance of the amino and carboxylate groups, of the histidine in leading to these dramatic conformational changes of the H-state. Further, comparison with previously published trypanosomatid HisRS structures reveals a pocket in the F-state of the parasite enzyme that may provide opportunities for developing specific inhibitors of Trypanosoma brucei HisRS. Comparison of histidine recognition in human and trypanosomatid histidyl-tRNA synthetases.,Koh CY, Wetzel AB, de van der Schueren WJ, Hol WG Biochimie. 2014 Nov;106:111-20. doi: 10.1016/j.biochi.2014.08.005. Epub 2014 Aug , 20. PMID:25151410[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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