Structure of human lysosomal acid α-glucosidase-a guide for the treatment of Pompe disease

Nat Commun. 2017 Oct 24;8(1):1111. doi: 10.1038/s41467-017-01263-3.


Pompe disease, a rare lysosomal storage disease caused by deficiency of the lysosomal acid α-glucosidase (GAA), is characterized by glycogen accumulation, triggering severe secondary cellular damage and resulting in progressive motor handicap and premature death. Numerous disease-causing mutations in the gaa gene have been reported, but the structural effects of the pathological variants were unknown. Here we present the high-resolution crystal structures of recombinant human GAA (rhGAA), the standard care of Pompe disease. These structures portray the unbound form of rhGAA and complexes thereof with active site-directed inhibitors, providing insight into substrate recognition and the molecular framework for the rationalization of the deleterious effects of disease-causing mutations. Furthermore, we report the structure of rhGAA in complex with the allosteric pharmacological chaperone N-acetylcysteine, which reveals the stabilizing function of this chaperone at the structural level.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylcysteine / chemistry
  • Acetylcysteine / metabolism
  • Catalytic Domain
  • Glycogen Storage Disease Type II / enzymology*
  • Glycogen Storage Disease Type II / genetics
  • Humans
  • Lysosomes / chemistry
  • Lysosomes / enzymology
  • Lysosomes / genetics
  • Models, Molecular
  • Protein Conformation
  • alpha-Glucosidases / chemistry*
  • alpha-Glucosidases / genetics
  • alpha-Glucosidases / metabolism


  • GAA protein, human
  • alpha-Glucosidases
  • Acetylcysteine