8CB1

Crystal structure of human lysosomal acid-alpha-glucosidase, GAA, in complex with N-PNT-DNM 15

8CB1 の概要

• エントリーDOI: 10.2210/pdb8cb1/pdb
• 分子名称: Lysosomal alpha-glucosidase (76 kDa), 1,2-ETHANEDIOL, (2R,3R,4R,5S)-2-(hydroxymethyl)-1-[5-(phenanthren-9-ylmethoxy)pentyl]piperidine-3,4,5-triol, ... (13 entities in total)
• 機能のキーワード: gaa, pompe disease, pharmacological chaperone, hydrolase
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 102042.72

構造登録者

Sulzenbacher, G.,Roig-Zamboni, V.,Overkleeft, H.,Artola, M. (登録日: 2023-01-25, 公開日: 2023-09-13, 最終更新日: 2024-10-23)

主引用文献

van der Gracht, D.,Rowland, R.J.,Roig-Zamboni, V.,Ferraz, M.J.,Louwerse, M.,Geurink, P.P.,Aerts, J.M.F.G.,Sulzenbacher, G.,Davies, G.J.,Overkleeft, H.S.,Artola, M.
Fluorescence polarisation activity-based protein profiling for the identification of deoxynojirimycin-type inhibitors selective for lysosomal retaining alpha- and beta-glucosidases.
Chem Sci, 14:9136-9144, 2023

PubMed Abstract: Lysosomal 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 β-glucosidase) or GH31 lysosomal retaining α-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 -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.

PubMed: 37655021
DOI: 10.1039/d3sc01021j

実験手法

X-RAY DIFFRACTION (1.75 Å)