title: Structure of acid beta-glucosidase with pharmacological chaperone provides insight into Gaucher disease.
abstract: Gaucher disease results from mutations in the lysosomal enzyme acid beta-glucosidase (GCase). Although enzyme replacement therapy has improved the health of some affected individuals, such as those with the prevalent N370S mutation, oral treatment with pharmacological chaperones may be therapeutic in a wider range of tissue compartments by restoring sufficient activity of endogenous mutant GCase. Here we demonstrate that isofagomine (IFG, 1) binds to the GCase active site, and both increases GCase activity in cell lysates and restores lysosomal trafficking in cells containing N370S mutant GCase. We also compare the crystal structures of IFG-bound GCase at low pH with those of glycerol-bound GCase at low pH and apo-GCase at neutral pH. Our data indicate that IFG induces active GCase, which is secured by interactions with Asn370. The design of small molecules that stabilize substrate-bound conformations of mutant proteins may be a general therapeutic strategy for diseases caused by protein misfolding and mistrafficking.
authors.affiliation: Structural Neurology Lab, Brigham and Women's Hospital and Harvard Medical School, 77 Ave Louis Pasteur, Boston, Massachusetts 02115, USA.
authors.forename: Raquel L
authors.initials: RL
authors.lastname: Lieberman
authors.forename: Brandon A
authors.initials: BA
authors.lastname: Wustman
authors.forename: Pedro
authors.initials: P
authors.lastname: Huertas
authors.forename: Allan C
authors.initials: AC
authors.lastname: Powe
authors.forename: Corey W
authors.initials: CW
authors.lastname: Pine
authors.forename: Richie
authors.initials: R
authors.lastname: Khanna
authors.forename: Michael G
authors.initials: MG
authors.lastname: Schlossmacher
authors.forename: Dagmar
authors.initials: D
authors.lastname: Ringe
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Petsko
mesh_terms: D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D005347:Fibroblasts / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D005776:Gaucher Disease / Q000188:drug therapy / Q000201:enzymology* / Q000378:metabolism; D005962:Glucosylceramidase / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D006860:Hydrogen Bonding; D006863:Hydrogen-Ion Concentration; D050112:Imino Pyranoses / Q000737:chemistry / Q000494:pharmacology; D008958:Models, Molecular; D010880:Piperidines / Q000737:chemistry* / Q000494:pharmacology; D011485:Protein Binding; D011487:Protein Conformation / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects
chemical_list: D004791:Enzyme Inhibitors; D050112:Imino Pyranoses; D010880:Piperidines; C098432:isofagomine; D005962:Glucosylceramidase; C090568:imiglucerase