4kqe

From Proteopedia

(Difference between revisions)

Revision as of 09:07, 7 December 2022

The mutant structure of the human glycyl-tRNA synthetase E71G

Structural highlights

4kqe is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

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

Glycyl-tRNA synthetase (GlyRS) is the enzyme that covalently links glycine to cognate tRNA for translation. It is of great research interest because of its nonconserved quaternary structures, unique species-specific aminoacylation properties, and noncanonical functions in neurological diseases, but none of these is fully understood. We report two crystal structures of human GlyRS variants, in the free form and in complex with tRNA(Gly) respectively, and reveal new aspects of the glycylation mechanism. We discover that insertion 3 differs considerably in conformation in catalysis and that it acts like a "switch" and fully opens to allow tRNA to bind in a cross-subunit fashion. The flexibility of the protein is supported by molecular dynamics simulation, as well as enzymatic activity assays. The biophysical and biochemical studies suggest that human GlyRS may utilize its flexibility for both the traditional function (regulate tRNA binding) and alternative functions (roles in diseases).

Large Conformational Changes of Insertion 3 in Human Glycyl-tRNA Synthetase (hGlyRS) during Catalysis.,Deng X, Qin X, Chen L, Jia Q, Zhang Y, Zhang Z, Lei D, Ren G, Zhou Z, Wang Z, Li Q, Xie W J Biol Chem. 2016 Mar 11;291(11):5740-52. doi: 10.1074/jbc.M115.679126. Epub 2016, Jan 21. PMID:26797133^[5]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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
↑ Deng X, Qin X, Chen L, Jia Q, Zhang Y, Zhang Z, Lei D, Ren G, Zhou Z, Wang Z, Li Q, Xie W. Large Conformational Changes of Insertion 3 in Human Glycyl-tRNA Synthetase (hGlyRS) during Catalysis. J Biol Chem. 2016 Mar 11;291(11):5740-52. doi: 10.1074/jbc.M115.679126. Epub 2016, Jan 21. PMID:26797133 doi:http://dx.doi.org/10.1074/jbc.M115.679126

1 Structural highlights
2 Disease
3 Function
4 Publication Abstract from PubMed
5 See Also
6 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/4kqe"

@@ Line 3: / Line 3: @@
 <StructureSection load='4kqe' size='340' side='right'caption='[[4kqe]], [[Resolution|resolution]] 2.74&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[4kqe]] is a 1 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=4KQE OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4KQE FirstGlance]. <br>
+<table><tr><td colspan='2'>[[4kqe]] 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=4KQE OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4KQE 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></td></tr>
+</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></td></tr>
-<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4kr2|4kr2]], [[4kr3|4kr3]]</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=4kqe FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4kqe OCA], [https://pdbe.org/4kqe PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4kqe RCSB], [https://www.ebi.ac.uk/pdbsum/4kqe PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4kqe ProSAT]</span></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='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://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4kqe FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4kqe OCA], [http://pdbe.org/4kqe PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4kqe RCSB], [http://www.ebi.ac.uk/pdbsum/4kqe PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4kqe ProSAT]</span></td></tr>
 </table>
 == 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 ==
-[[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;">
 == Publication Abstract from PubMed ==
@@ Line 30: / Line 27: @@
 __TOC__
 </StructureSection>
-[[Category: Glycine--tRNA ligase]]
+[[Category: Homo sapiens]]
-[[Category: Human]]
 [[Category: Large Structures]]
-[[Category: Hao, Z]]
+[[Category: Hao Z]]
-[[Category: Qin, X]]
+[[Category: Qin X]]
-[[Category: Tian, Q]]
+[[Category: Tian Q]]
-[[Category: Xie, W]]
+[[Category: Xie W]]
-[[Category: Zhang, Z]]
+[[Category: Zhang Z]]
-[[Category: Zhou, C]]
+[[Category: Zhou C]]
-[[Category: Aminoacylation]]
-[[Category: Ligase]]
-[[Category: Rossmann fold]]
-[[Category: Trna-gly]]

4kqe

From Proteopedia

Revision as of 09:07, 7 December 2022

The mutant structure of the human glycyl-tRNA synthetase E71G

Structural highlights

Disease

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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