7p32 | pdb_00007p32

Crystal structure of human lysosomal acid-alpha-glucosidase, GAA, in complex with cyclosulfamidate 6

spinqualitylabelsall models 7p32, resolution 1.82Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 7p32 is a 1 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: 56I, BMA, CL, EDO, GOL, NAG, PGE, SO4, FUC NonStd Res: CSO Related: 7p2z Activity: Alpha-glucosidase, with EC number 3.2.1.20 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease [LYAG_HUMAN] Glycogen storage disease due to acid maltase deficiency, infantile onset;Glycogen storage disease due to acid maltase deficiency, juvenile onset;Glycogen storage disease due to acid maltase deficiency, adult onset. The disease is caused by mutations affecting the gene represented in this entry. Function [LYAG_HUMAN] Essential for the degradation of glygogen to glucose in lysosomes. Publication Abstract from PubMed alpha-Glucosidase inhibitors are potential therapeutics for the treatment of diabetes, viral infections, and Pompe disease. Herein, we report a 1,6-epi-cyclophellitol cyclosulfamidate as a new class of reversible alpha-glucosidase inhibitors that displays enzyme inhibitory activity by virtue of its conformational mimicry of the substrate when bound in the Michaelis complex. The alpha-d-glc-configured cyclophellitol cyclosulfamidate 4 binds in a competitive manner the human lysosomal acid alpha-glucosidase (GAA), ER alpha-glucosidases, and, at higher concentrations, intestinal alpha-glucosidases, displaying an excellent selectivity over the human beta-glucosidases GBA and GBA2 and glucosylceramide synthase (GCS). Cyclosulfamidate 4 stabilizes recombinant human GAA (rhGAA, alglucosidase alfa, Myozyme) in cell medium and plasma and facilitates enzyme trafficking to lysosomes. It stabilizes rhGAA more effectively than existing small-molecule chaperones and does so in vitro, in cellulo, and in vivo in zebrafish, thus representing a promising therapeutic alternative to Miglustat for Pompe disease. 1,6-epi-Cyclophellitol Cyclosulfamidate Is a Bona Fide Lysosomal alpha-Glucosidase Stabilizer for the Treatment of Pompe Disease.,Kok K, Kuo CL, Katzy RE, Lelieveld LT, Wu L, Roig-Zamboni V, van der Marel GA, Codee JDC, Sulzenbacher G, Davies GJ, Overkleeft HS, Aerts JMFG, Artola M J Am Chem Soc. 2022 Aug 17;144(32):14819-14827. doi: 10.1021/jacs.2c05666. Epub, 2022 Aug 2. PMID:35917590 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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