7P2Z

Crystal structure of human lysosomal acid-alpha-glucosidase, GAA, in complex with cyclosulfamidate 4

This is a non-PDB format compatible entry.

Summary for 7P2Z

• Entry DOI: 10.2210/pdb7p2z/pdb
• Descriptor: Lysosomal alpha-glucosidase, (3~{a}~{R},4~{S},5~{S},6~{S},7~{R},7~{a}~{S})-7-(hydroxymethyl)-2,2-bis(oxidanylidene)-3~{a},4,5,6,7,7~{a}-hexahydro-3~{H}-benzo[d][1,2,3]oxathiazole-4,5,6-triol, TRIETHYLENE GLYCOL, ... (12 entities in total)
• Functional Keywords: alpha-glycosidase, lysosomal, pompe disease, pharmacological chaperone, hydrolase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 198272.11

Authors

Roig-Zamboni, V.,Kok, K.,Overkleeft, H.,Artola, M.,Sulzenbacher, G. (deposition date: 2021-07-06, release date: 2022-07-13, Last modification date: 2024-11-13)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (1.85 Å)