6r4g

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'''Unreleased structure'''
 
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The entry 6r4g is ON HOLD until Paper Publication
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==Crystal structure of human GFAT-1 in complex with UDP-GlcNAc==
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<StructureSection load='6r4g' size='340' side='right'caption='[[6r4g]], [[Resolution|resolution]] 2.50&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[6r4g]] is a 2 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=6R4G OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6R4G FirstGlance]. <br>
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=G6Q:GLUCOSE-6-PHOSPHATE'>G6Q</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=UD1:URIDINE-DIPHOSPHATE-N-ACETYLGLUCOSAMINE'>UD1</scene></td></tr>
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<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">GFPT1, GFAT, GFPT ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
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<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Glutamine--fructose-6-phosphate_transaminase_(isomerizing) Glutamine--fructose-6-phosphate transaminase (isomerizing)], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.6.1.16 2.6.1.16] </span></td></tr>
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<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=6r4g FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6r4g OCA], [http://pdbe.org/6r4g PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6r4g RCSB], [http://www.ebi.ac.uk/pdbsum/6r4g PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6r4g ProSAT]</span></td></tr>
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</table>
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== Disease ==
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[[http://www.uniprot.org/uniprot/GFPT1_HUMAN GFPT1_HUMAN]] Defects in GFPT1 are the cause of myasthenia, congenital, with tubular aggregates, type 1 (CMSTA1) [MIM:[http://omim.org/entry/610542 610542]]. A congenital myasthenic syndrome characterized by onset of proximal muscle weakness in the first decade. Individuals with this condition have a recognizable pattern of weakness of shoulder and pelvic girdle muscles, and sparing of ocular or facial muscles. EMG classically shows a decremental response to repeated nerve stimulation, a sign of neuromuscular junction dysfunction. Affected individuals show a favorable response to acetylcholinesterase (AChE) inhibitors.<ref>PMID:21310273</ref>
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== Function ==
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[[http://www.uniprot.org/uniprot/GFPT1_HUMAN GFPT1_HUMAN]] Controls the flux of glucose into the hexosamine pathway. Most likely involved in regulating the availability of precursors for N- and O-linked glycosylation of proteins.
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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Glutamine fructose-6-phosphate amidotransferase (GFAT) is the key enzyme in the hexosamine pathway (HP) that produces uridine 5'-diphospho-N-acetyl-D-glucosamine (UDP-GlcNAc), linking energy metabolism with posttranslational protein glycosylation. In Caenorhabditis elegans, we previously identified gfat-1 gain-of-function mutations that elevate UDP-GlcNAc levels, improve protein homeostasis, and extend lifespan. GFAT is highly conserved, but the gain-of-function mechanism and its relevance in mammalian cells remained unclear. Here, we present the full-length crystal structure of human GFAT-1 in complex with various ligands and with important mutations. UDP-GlcNAc directly interacts with GFAT-1, inhibiting catalytic activity. The longevity-associated G451E variant shows drastically reduced sensitivity to UDP-GlcNAc inhibition in enzyme activity assays. Our structural and functional data point to a critical role of the interdomain linker in UDP-GlcNAc inhibition. In mammalian cells, the G451E variant potently activates the HP. Therefore, GFAT-1 gain-of-function through loss of feedback inhibition constitutes a potential target for the treatment of age-related proteinopathies.
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Authors:
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Loss of GFAT-1 feedback regulation activates the hexosamine pathway that modulates protein homeostasis.,Ruegenberg S, Horn M, Pichlo C, Allmeroth K, Baumann U, Denzel MS Nat Commun. 2020 Feb 4;11(1):687. doi: 10.1038/s41467-020-14524-5. PMID:32019926<ref>PMID:32019926</ref>
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Description:
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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[[Category: Unreleased Structures]]
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</div>
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<div class="pdbe-citations 6r4g" style="background-color:#fffaf0;"></div>
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== References ==
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<references/>
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__TOC__
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</StructureSection>
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[[Category: Human]]
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[[Category: Large Structures]]
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[[Category: Allmeroth, K]]
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[[Category: Baumann, U]]
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[[Category: Denzel, M S]]
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[[Category: Horn, M]]
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[[Category: Pichlo, C]]
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[[Category: Ruegenberg, S]]
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[[Category: Gfat]]
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[[Category: Glutamine fructose-6-phosphate aminotransferase]]
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[[Category: Ntn hydrolase]]
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[[Category: Transferase]]

Revision as of 07:29, 19 February 2020

Crystal structure of human GFAT-1 in complex with UDP-GlcNAc

PDB ID 6r4g

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