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6r4e
From Proteopedia
(Difference between revisions)
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| - | '''Unreleased structure''' | ||
| - | + | ==Crystal structure of human GFAT-1 in complex with Glucose-6-Phosphate and L-Glu== | |
| + | <StructureSection load='6r4e' size='340' side='right'caption='[[6r4e]], [[Resolution|resolution]] 2.35Å' scene=''> | ||
| + | == Structural highlights == | ||
| + | <table><tr><td colspan='2'>[[6r4e]] 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=6R4E OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6R4E FirstGlance]. <br> | ||
| + | </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=GLU:GLUTAMIC+ACID'>GLU</scene></td></tr> | ||
| + | <tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=SEP:PHOSPHOSERINE'>SEP</scene></td></tr> | ||
| + | <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> | ||
| + | <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> | ||
| + | <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=6r4e FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6r4e OCA], [http://pdbe.org/6r4e PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6r4e RCSB], [http://www.ebi.ac.uk/pdbsum/6r4e PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6r4e ProSAT]</span></td></tr> | ||
| + | </table> | ||
| + | == Disease == | ||
| + | [[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> | ||
| + | == Function == | ||
| + | [[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. | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | 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. | ||
| - | + | 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> | |
| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| - | [[Category: | + | </div> |
| + | <div class="pdbe-citations 6r4e" style="background-color:#fffaf0;"></div> | ||
| + | == References == | ||
| + | <references/> | ||
| + | __TOC__ | ||
| + | </StructureSection> | ||
| + | [[Category: Human]] | ||
| + | [[Category: Large Structures]] | ||
| + | [[Category: Allmeroth, K]] | ||
| + | [[Category: Baumann, U]] | ||
| + | [[Category: Denzel, M S]] | ||
| + | [[Category: Horn, M]] | ||
| + | [[Category: Pichlo, C]] | ||
| + | [[Category: Ruegenberg, S]] | ||
| + | [[Category: Gfat]] | ||
| + | [[Category: Glutamine fructose-6-phosphate aminotransferase]] | ||
| + | [[Category: Ntn hydrolase]] | ||
| + | [[Category: Transferase]] | ||
Revision as of 07:29, 19 February 2020
Crystal structure of human GFAT-1 in complex with Glucose-6-Phosphate and L-Glu
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