|
|
| (15 intermediate revisions not shown.) |
| Line 1: |
Line 1: |
| - | [[Image:2q5h.jpg|left|200px]]<br /><applet load="2q5h" size="350" color="white" frame="true" align="right" spinBox="true" | |
| - | caption="2q5h, resolution 3.0Å" /> | |
| - | '''Crystal structure of apo-wildtype Glycyl-tRNA synthetase'''<br /> | |
| | | | |
| - | ==Overview== | + | ==Crystal structure of apo-wildtype Glycyl-tRNA synthetase== |
| - | Dominant mutations in the ubiquitous enzyme glycyl-tRNA synthetase, (GlyRS), including S581L, lead to motor nerve degeneration. We have, determined crystal structures of wildtype and S581L-mutant human GlyRS., The S581L mutation is approximately 50A from the active site, and yet, gives reduced aminoacylation activity. The overall structures of wildtype, and S581L-GlyRS, including the active site, are very similar. However, residues 567-575 of the anticodon-binding domain shift position and in, turn could indirectly affect glycine binding via the tRNA or alternatively, inhibit conformational changes. Reduced enzyme activity may underlie, neuronal degeneration, although a dominant-negative effect is more likely, in this autosomal dominant disorder. | + | <StructureSection load='2q5h' size='340' side='right'caption='[[2q5h]], [[Resolution|resolution]] 3.00Å' scene=''> |
| | + | == Structural highlights == |
| | + | <table><tr><td colspan='2'>[[2q5h]] is a 1 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=2Q5H OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2Q5H 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]] 3Å</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=2q5h FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2q5h OCA], [https://pdbe.org/2q5h PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2q5h RCSB], [https://www.ebi.ac.uk/pdbsum/2q5h PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2q5h ProSAT]</span></td></tr> |
| | + | </table> |
| | + | == Disease == |
| | + | [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 == |
| | + | [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> |
| | + | == Evolutionary Conservation == |
| | + | [[Image:Consurf_key_small.gif|200px|right]] |
| | + | Check<jmol> |
| | + | <jmolCheckbox> |
| | + | <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/q5/2q5h_consurf.spt"</scriptWhenChecked> |
| | + | <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked> |
| | + | <text>to colour the structure by Evolutionary Conservation</text> |
| | + | </jmolCheckbox> |
| | + | </jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=2q5h ConSurf]. |
| | + | <div style="clear:both"></div> |
| | + | <div style="background-color:#fffaf0;"> |
| | + | == Publication Abstract from PubMed == |
| | + | Dominant mutations in the ubiquitous enzyme glycyl-tRNA synthetase (GlyRS), including S581L, lead to motor nerve degeneration. We have determined crystal structures of wildtype and S581L-mutant human GlyRS. The S581L mutation is approximately 50A from the active site, and yet gives reduced aminoacylation activity. The overall structures of wildtype and S581L-GlyRS, including the active site, are very similar. However, residues 567-575 of the anticodon-binding domain shift position and in turn could indirectly affect glycine binding via the tRNA or alternatively inhibit conformational changes. Reduced enzyme activity may underlie neuronal degeneration, although a dominant-negative effect is more likely in this autosomal dominant disorder. |
| | | | |
| - | ==About this Structure==
| + | Crystal structure of human wildtype and S581L-mutant glycyl-tRNA synthetase, an enzyme underlying distal spinal muscular atrophy.,Cader MZ, Ren J, James PA, Bird LE, Talbot K, Stammers DK FEBS Lett. 2007 Jun 26;581(16):2959-64. Epub 2007 May 29. PMID:17544401<ref>PMID:17544401</ref> |
| - | 2Q5H is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Active as [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] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2Q5H OCA].
| + | |
| | | | |
| - | ==Reference==
| + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> |
| - | Crystal structure of human wildtype and S581L-mutant glycyl-tRNA synthetase, an enzyme underlying distal spinal muscular atrophy., Cader MZ, Ren J, James PA, Bird LE, Talbot K, Stammers DK, FEBS Lett. 2007 Jun 26;581(16):2959-2964. Epub 2007 May 29. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=17544401 17544401]
| + | </div> |
| - | [[Category: Glycine--tRNA ligase]]
| + | <div class="pdbe-citations 2q5h" style="background-color:#fffaf0;"></div> |
| - | [[Category: Homo sapiens]]
| + | |
| - | [[Category: Single protein]]
| + | |
| - | [[Category: Bird, L.E.]]
| + | |
| - | [[Category: Cader, M.Z.]]
| + | |
| - | [[Category: James, P.A.]]
| + | |
| - | [[Category: OPPF, Oxford.Protein.Production.Facility.]]
| + | |
| - | [[Category: Ren, J.]]
| + | |
| - | [[Category: Stammers, D.K.]]
| + | |
| - | [[Category: Talbot, K.]]
| + | |
| - | [[Category: aminoacyl-trna synthetase]]
| + | |
| - | [[Category: atp-binding]]
| + | |
| - | [[Category: glycyl-trna synthetase]]
| + | |
| - | [[Category: oppf]]
| + | |
| - | [[Category: oxford protein production facility]]
| + | |
| - | [[Category: structural genomics]]
| + | |
| | | | |
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Wed Jan 23 14:23:26 2008''
| + | ==See Also== |
| | + | *[[Aminoacyl tRNA synthetase 3D structures|Aminoacyl tRNA synthetase 3D structures]] |
| | + | == References == |
| | + | <references/> |
| | + | __TOC__ |
| | + | </StructureSection> |
| | + | [[Category: Homo sapiens]] |
| | + | [[Category: Large Structures]] |
| | + | [[Category: Bird LE]] |
| | + | [[Category: Cader MZ]] |
| | + | [[Category: James PA]] |
| | + | [[Category: Ren J]] |
| | + | [[Category: Stammers DK]] |
| | + | [[Category: Talbot K]] |
| 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]
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
Dominant mutations in the ubiquitous enzyme glycyl-tRNA synthetase (GlyRS), including S581L, lead to motor nerve degeneration. We have determined crystal structures of wildtype and S581L-mutant human GlyRS. The S581L mutation is approximately 50A from the active site, and yet gives reduced aminoacylation activity. The overall structures of wildtype and S581L-GlyRS, including the active site, are very similar. However, residues 567-575 of the anticodon-binding domain shift position and in turn could indirectly affect glycine binding via the tRNA or alternatively inhibit conformational changes. Reduced enzyme activity may underlie neuronal degeneration, although a dominant-negative effect is more likely in this autosomal dominant disorder.
Crystal structure of human wildtype and S581L-mutant glycyl-tRNA synthetase, an enzyme underlying distal spinal muscular atrophy.,Cader MZ, Ren J, James PA, Bird LE, Talbot K, Stammers DK FEBS Lett. 2007 Jun 26;581(16):2959-64. Epub 2007 May 29. PMID:17544401[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
- ↑ 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
|
