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| | <StructureSection load='5e6m' size='340' side='right'caption='[[5e6m]], [[Resolution|resolution]] 2.93Å' scene=''> | | <StructureSection load='5e6m' size='340' side='right'caption='[[5e6m]], [[Resolution|resolution]] 2.93Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5e6m]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5E6M OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=5E6M FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5e6m]] 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=5E6M OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5E6M FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GAP:GLYCYL-ADENOSINE-5-PHOSPHATE'>GAP</scene>, <scene name='pdbligand=NI:NICKEL+(II)+ION'>NI</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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]] 2.927Å</td></tr> |
| - | <tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=GTP:GUANOSINE-5-TRIPHOSPHATE'>GTP</scene></td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GAP:GLYCYL-ADENOSINE-5-PHOSPHATE'>GAP</scene>, <scene name='pdbligand=GTP:GUANOSINE-5-TRIPHOSPHATE'>GTP</scene>, <scene name='pdbligand=NI:NICKEL+(II)+ION'>NI</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">GARS ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=5e6m FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5e6m OCA], [https://pdbe.org/5e6m PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5e6m RCSB], [https://www.ebi.ac.uk/pdbsum/5e6m PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5e6m ProSAT]</span></td></tr> |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Glycine--tRNA_ligase Glycine--tRNA ligase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=6.1.1.14 6.1.1.14] </span></td></tr> | + | |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=5e6m FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5e6m OCA], [http://pdbe.org/5e6m PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5e6m RCSB], [http://www.ebi.ac.uk/pdbsum/5e6m PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5e6m ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Disease == | | == Disease == |
| - | [[http://www.uniprot.org/uniprot/SYG_HUMAN SYG_HUMAN]] Defects in GARS are the cause of Charcot-Marie-Tooth disease type 2D (CMT2D) [MIM:[http://omim.org/entry/601472 601472]]. CMT2D is a form of Charcot-Marie-Tooth disease, the most common inherited disorder of the peripheral nervous system. Charcot-Marie-Tooth disease is classified in two main groups on the basis of electrophysiologic properties and histopathology: primary peripheral demyelinating neuropathy or CMT1, and primary peripheral axonal neuropathy or CMT2. Neuropathies of the CMT2 group are characterized by signs of axonal regeneration in the absence of obvious myelin alterations, normal or slightly reduced nerve conduction velocities, and progressive distal muscle weakness and atrophy. CMT2D is characterized by a more severe phenotype in the upper extremities (severe weakness and atrophy, absence of tendon reflexes) than in the lower limbs. CMT2D inheritance is autosomal dominant.<ref>PMID:12690580</ref> Defects in GARS are a cause of distal hereditary motor neuronopathy type 5A (HMN5A) [MIM:[http://omim.org/entry/600794 600794]]; also known as distal hereditary motor neuropathy type V (DSMAV). A disorder characterized by distal muscular atrophy mainly affecting the upper extremities, in contrast to other distal motor neuronopathies. These constitute a heterogeneous group of neuromuscular diseases caused by selective degeneration of motor neurons in the anterior horn of the spinal cord, without sensory deficit in the posterior horn. The overall clinical picture consists of a classical distal muscular atrophy syndrome in the legs without clinical sensory loss. The disease starts with weakness and wasting of distal muscles of the anterior tibial and peroneal compartments of the legs. Later on, weakness and atrophy may expand to the proximal muscles of the lower limbs and/or to the distal upper limbs.<ref>PMID:12690580</ref> | + | [https://www.uniprot.org/uniprot/GARS_HUMAN GARS_HUMAN] Autosomal dominant Charcot-Marie-Tooth disease type 2D;Distal hereditary motor neuropathy type 5. 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. The disease is caused by variants affecting the gene represented in this entry. |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/SYG_HUMAN SYG_HUMAN]] Catalyzes the attachment of glycine to tRNA(Gly). Is also able produce diadenosine tetraphosphate (Ap4A), a universal pleiotropic signaling molecule needed for cell regulation pathways, by direct condensation of 2 ATPs.<ref>PMID:19710017</ref> | + | [https://www.uniprot.org/uniprot/GARS_HUMAN GARS_HUMAN] Catalyzes the ATP-dependent ligation of glycine to the 3'-end of its cognate tRNA, via the formation of an aminoacyl-adenylate intermediate (Gly-AMP) (PubMed:17544401, PubMed:28675565, PubMed:24898252). Also produces diadenosine tetraphosphate (Ap4A), a universal pleiotropic signaling molecule needed for cell regulation pathways, by direct condensation of 2 ATPs. Thereby, may play a special role in Ap4A homeostasis (PubMed:19710017).<ref>PMID:17544401</ref> <ref>PMID:19710017</ref> <ref>PMID:24898252</ref> <ref>PMID:28675565</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Glycine--tRNA ligase]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Human]]
| + | |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Chen, L]] | + | [[Category: Chen L]] |
| - | [[Category: Deng, X]] | + | [[Category: Deng X]] |
| - | [[Category: Liu, Y]] | + | [[Category: Liu Y]] |
| - | [[Category: Qin, X]] | + | [[Category: Qin X]] |
| - | [[Category: Xie, W]] | + | [[Category: Xie W]] |
| - | [[Category: Aminoacyl-trna synthese]]
| + | |
| - | [[Category: Glycyl-trna synthetase]]
| + | |
| - | [[Category: Ligase-rna complex]]
| + | |
| - | [[Category: Trna]]
| + | |
| Structural highlights
Disease
GARS_HUMAN Autosomal dominant Charcot-Marie-Tooth disease type 2D;Distal hereditary motor neuropathy type 5. 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. The disease is caused by variants affecting the gene represented in this entry.
Function
GARS_HUMAN Catalyzes the ATP-dependent ligation of glycine to the 3'-end of its cognate tRNA, via the formation of an aminoacyl-adenylate intermediate (Gly-AMP) (PubMed:17544401, PubMed:28675565, PubMed:24898252). Also produces diadenosine tetraphosphate (Ap4A), a universal pleiotropic signaling molecule needed for cell regulation pathways, by direct condensation of 2 ATPs. Thereby, may play a special role in Ap4A homeostasis (PubMed:19710017).[1] [2] [3] [4]
Publication Abstract from PubMed
Aminoacyl-tRNA synthetases are essential components of the protein translational machinery in all living species, among which the human glycyl-tRNA synthetase (hGlyRS) is of great research interest because of its unique species-specific aminoacylation properties and noncanonical roles in the Charcot-Marie-Tooth neurological disease. However, the molecular mechanisms of how the enzyme carries out its classical and alternative functions are not well understood. Here, we report a complex structure of the wild-type hGlyRS bound with tRNAGly at 2.95A. In the complex, the flexible Whep-TRS domain is visible in one of the subunits of the enzyme dimer, and the tRNA molecule is also completely resolved. At the active site, a glycyl-AMP molecule is synthesized and is waiting for the transfer of the glycyl moiety to occur. This cocrystal structure provides us with new details about the recognition mechanism in the intermediate stage during glycylation, which was not well elucidated in the previous crystal structures where the inhibitor AMPPNP was used for crystallization. More importantly, the structural and biochemical work conducted in the current and previous studies allows us to build a model of the full-length hGlyRS in complex with tRNAGly, which greatly helps us to understand the roles that insertions and the Whep-TRS domain play in the tRNA-binding process. Finally, through structure comparison with other class II aminoacyl-tRNA synthetases bound with their tRNA substrates, we found some commonalities of the aminoacylation mechanism between these enzymes.
Crystal Structure of the Wild-Type Human GlyRS Bound with tRNAGly in a Productive Conformation.,Qin X, Deng X, Chen L, Xie W J Mol Biol. 2016 May 31. pii: S0022-2836(16)30187-5. doi:, 10.1016/j.jmb.2016.05.018. PMID:27261259[5]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Cader MZ, Ren J, James PA, Bird LE, Talbot K, Stammers DK. Crystal structure of human wildtype and S581L-mutant glycyl-tRNA synthetase, an enzyme underlying distal spinal muscular atrophy. FEBS Lett. 2007 Jun 26;581(16):2959-64. Epub 2007 May 29. PMID:17544401 doi:10.1016/j.febslet.2007.05.046
- ↑ Guo RT, Chong YE, Guo M, Yang XL. Crystal structures and biochemical analyses suggest a unique mechanism and role for human glycyl-tRNA synthetase in Ap4A homeostasis. J Biol Chem. 2009 Oct 16;284(42):28968-76. Epub 2009 Aug 26. PMID:19710017 doi:10.1074/jbc.M109.030692
- ↑ Qin X, Hao Z, Tian Q, Zhang Z, Zhou C, Xie W. Cocrystal Structures of Glycyl-tRNA Synthetase in Complex with tRNA Suggest Multiple Conformational States in Glycylation. J Biol Chem. 2014 Jul 18;289(29):20359-69. doi: 10.1074/jbc.M114.557249. Epub, 2014 Jun 4. PMID:24898252 doi:http://dx.doi.org/10.1074/jbc.M114.557249
- ↑ Oprescu SN, Chepa-Lotrea X, Takase R, Golas G, Markello TC, Adams DR, Toro C, Gropman AL, Hou YM, Malicdan MCV, Gahl WA, Tifft CJ, Antonellis A. Compound heterozygosity for loss-of-function GARS variants results in a multisystem developmental syndrome that includes severe growth retardation. Hum Mutat. 2017 Oct;38(10):1412-1420. doi: 10.1002/humu.23287. Epub 2017 Jul 14. PMID:28675565 doi:http://dx.doi.org/10.1002/humu.23287
- ↑ Qin X, Deng X, Chen L, Xie W. Crystal Structure of the Wild-Type Human GlyRS Bound with tRNAGly in a Productive Conformation. J Mol Biol. 2016 May 31. pii: S0022-2836(16)30187-5. doi:, 10.1016/j.jmb.2016.05.018. PMID:27261259 doi:http://dx.doi.org/10.1016/j.jmb.2016.05.018
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