8cb1
Crystal structure of human lysosomal acid-alpha-glucosidase, GAA, in complex with N-PNT-DNM 15
Structural highlights
DiseaseLYAG_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. FunctionLYAG_HUMAN Essential for the degradation of glygogen to glucose in lysosomes. Publication Abstract from PubMedLysosomal exoglycosidases are responsible for processing endocytosed glycans from the non-reducing end to produce the corresponding monosaccharides. Genetic mutations in a particular lysosomal glycosidase may result in accumulation of its particular substrate, which may cause diverse lysosomal storage disorders. The identification of effective therapeutic modalities to treat these diseases is a major yet poorly realised objective in biomedicine. One common strategy comprises the identification of effective and selective competitive inhibitors that may serve to stabilize the proper folding of the mutated enzyme, either during maturation and trafficking to, or residence in, endo-lysosomal compartments. The discovery of such inhibitors is greatly aided by effective screening assays, the development of which is the focus of the here-presented work. We developed and applied fluorescent activity-based probes reporting on either human GH30 lysosomal glucosylceramidase (GBA1, a retaining beta-glucosidase) or GH31 lysosomal retaining alpha-glucosidase (GAA). FluoPol-ABPP screening of our in-house 358-member iminosugar library yielded compound classes selective for either of these enzymes. In particular, we identified a class of N-alkyldeoxynojirimycins that inhibit GAA, but not GBA1, and that may form the starting point for the development of pharmacological chaperone therapeutics for the lysosomal glycogen storage disease that results from genetic deficiency in GAA: Pompe disease. Fluorescence polarisation activity-based protein profiling for the identification of deoxynojirimycin-type inhibitors selective for lysosomal retaining alpha- and beta-glucosidases.,van der Gracht D, Rowland RJ, Roig-Zamboni V, Ferraz MJ, Louwerse M, Geurink PP, Aerts JMFG, Sulzenbacher G, Davies GJ, Overkleeft HS, Artola M Chem Sci. 2023 Aug 8;14(34):9136-9144. doi: 10.1039/d3sc01021j. eCollection 2023 , Aug 30. PMID:37655021[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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