6r4j | pdb_00006r4j

Crystal structure of human GFAT-1 G451E in complex with UDP-GlcNAc

spinqualitylabelsall models 6r4j, resolution 2.42Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6r4j is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.42Å Ligands: G6Q, GLU, MG, UD1 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease GFPT1_HUMAN Defects in GFPT1 are the cause of myasthenia, congenital, with tubular aggregates, type 1 (CMSTA1) [MIM: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. Function 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. 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 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Aminotransferase 3D structures

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