7P32

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

これはPDB形式変換不可エントリーです。

7P32 の概要

• エントリーDOI: 10.2210/pdb7p32/pdb
• 関連するPDBエントリー: 7P2Z
• 分子名称: Lysosomal alpha-glucosidase, GLYCEROL, 1,2-ETHANEDIOL, ... (13 entities in total)
• 機能のキーワード: alpha-glycosidase, lysosomal, pompe disease, pharmacological chaperone, hydrolase
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 100880.06

構造登録者

Roig-Zamboni, V.,Kok, K.,Overkleeft, H.,Artola, M.,Sulzenbacher, G. (登録日: 2021-07-06, 公開日: 2022-07-13, 最終更新日: 2024-11-13)

主引用文献

Kok, K.,Kuo, C.L.,Katzy, R.E.,Lelieveld, L.T.,Wu, L.,Roig-Zamboni, V.,van der Marel, G.A.,Codee, J.D.C.,Sulzenbacher, G.,Davies, G.J.,Overkleeft, H.S.,Aerts, J.M.F.G.,Artola, M.
1,6- epi-Cyclophellitol Cyclosulfamidate Is a Bona Fide Lysosomal alpha-Glucosidase Stabilizer for the Treatment of Pompe Disease.
J.Am.Chem.Soc., 144:14819-14827, 2022

PubMed Abstract: α-Glucosidase inhibitors are potential therapeutics for the treatment of diabetes, viral infections, and Pompe disease. Herein, we report a 1,6--cyclophellitol cyclosulfamidate as a new class of reversible α-glucosidase inhibitors that displays enzyme inhibitory activity by virtue of its conformational mimicry of the substrate when bound in the Michaelis complex. The α-d-configured cyclophellitol cyclosulfamidate binds in a competitive manner the human lysosomal acid α-glucosidase (GAA), ER α-glucosidases, and, at higher concentrations, intestinal α-glucosidases, displaying an excellent selectivity over the human β-glucosidases GBA and GBA2 and glucosylceramide synthase (GCS). Cyclosulfamidate 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 , , and in zebrafish, thus representing a promising therapeutic alternative to Miglustat for Pompe disease.

PubMed: 35917590
DOI: 10.1021/jacs.2c05666

実験手法

X-RAY DIFFRACTION (1.82 Å)