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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 [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4PHC FirstGlance]. <br> | + | <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='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=HIS:HISTIDINE'>HIS</scene></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]] 2.844Å</td></tr> |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Histidine--tRNA_ligase Histidine--tRNA ligase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=6.1.1.21 6.1.1.21] </span></td></tr> | + | <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'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4phc FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4phc OCA], [http://pdbe.org/4phc PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4phc RCSB], [http://www.ebi.ac.uk/pdbsum/4phc PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4phc ProSAT]</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=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 == |
| - | [[http://www.uniprot.org/uniprot/SYHC_HUMAN SYHC_HUMAN]] Defects in HARS are a cause of Usher syndrome type 3B (USH3B) [MIM:[http://omim.org/entry/614504 614504]]. USH3B is a syndrome characterized by progressive vision and hearing loss during early childhood. Some patients have the so-called 'Charles Bonnet syndrome,' involving decreased visual acuity and vivid visual hallucinations. USH is a genetically heterogeneous condition characterized by the association of retinitis pigmentosa with sensorineural deafness. Age at onset and differences in auditory and vestibular function distinguish Usher syndrome type 1 (USH1), Usher syndrome type 2 (USH2) and Usher syndrome type 3 (USH3). USH3 is characterized by postlingual, progressive hearing loss, variable vestibular dysfunction, and onset of retinitis pigmentosa symptoms, including nyctalopia, constriction of the visual fields, and loss of central visual acuity, usually by the second decade of life.<ref>PMID:22279524</ref> Note=HARS mutations may be involved in peripheral neuropathy, a disease mainly characterized by distal motor and sensory dysfunction. Inherited peripheral neuropathies are clinically and genetically heterogeneous with variable age of onset and reduced penetrance associated with specific loci. HARS mutations may directly predispose patients to peripheral neuropathy or may modify a peripheral neuropathy phenotype by contributing to the genetic and environmental load in a given patient (PubMed:22930593). | + | [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;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | </div> | | </div> |
| | <div class="pdbe-citations 4phc" style="background-color:#fffaf0;"></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: Histidine--tRNA ligase]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Hol, W G.J]] | + | [[Category: Large Structures]] |
| - | [[Category: Koh, C Y]] | + | [[Category: Hol WGJ]] |
| - | [[Category: Schueren, W J.de van der]] | + | [[Category: Koh CY]] |
| - | [[Category: Wetzel, A B]] | + | [[Category: Wetzel AB]] |
| - | [[Category: Aar]] | + | [[Category: De van der Schueren WJ]] |
| - | [[Category: Aminoacyl-trna synthetase]]
| + | |
| - | [[Category: Cytoplasmic]]
| + | |
| - | [[Category: Hisr]]
| + | |
| - | [[Category: Human]]
| + | |
| - | [[Category: Ligase]]
| + | |
| - | [[Category: Nucleotide binding]]
| + | |
| - | [[Category: Protein-substrate complex]]
| + | |
| - | [[Category: Rossmann-fold]]
| + | |
| - | [[Category: Translation]]
| + | |
| Structural highlights
Disease
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
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).[1] [2]
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[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Safka Brozkova D, Deconinck T, Griffin LB, Ferbert A, Haberlova J, Mazanec R, Lassuthova P, Roth C, Pilunthanakul T, Rautenstrauss B, Janecke AR, Zavadakova P, Chrast R, Rivolta C, Zuchner S, Antonellis A, Beg AA, De Jonghe P, Senderek J, Seeman P, Baets J. Loss of function mutations in HARS cause a spectrum of inherited peripheral neuropathies. Brain. 2015 Aug;138(Pt 8):2161-72. doi: 10.1093/brain/awv158. Epub 2015 Jun 13. PMID:26072516 doi:http://dx.doi.org/10.1093/brain/awv158
- ↑ Abbott JA, Meyer-Schuman R, Lupo V, Feely S, Mademan I, Oprescu SN, Griffin LB, Alberti MA, Casasnovas C, Aharoni S, Basel-Vanagaite L, Zuchner S, De Jonghe P, Baets J, Shy ME, Espinos C, Demeler B, Antonellis A, Francklyn C. Substrate interaction defects in histidyl-tRNA synthetase linked to dominant axonal peripheral neuropathy. Hum Mutat. 2018 Mar;39(3):415-432. doi: 10.1002/humu.23380. Epub 2017 Dec 26. PMID:29235198 doi:http://dx.doi.org/10.1002/humu.23380
- ↑ Koh CY, Wetzel AB, de van der Schueren WJ, Hol WG. Comparison of histidine recognition in human and trypanosomatid histidyl-tRNA synthetases. Biochimie. 2014 Nov;106:111-20. doi: 10.1016/j.biochi.2014.08.005. Epub 2014 Aug , 20. PMID:25151410 doi:http://dx.doi.org/10.1016/j.biochi.2014.08.005
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