2nsx

Structure of acid-beta-glucosidase with pharmacological chaperone provides insight into Gaucher diseaseStructure of acid-beta-glucosidase with pharmacological chaperone provides insight into Gaucher disease

Publication Abstract from PubMed

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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.

Structure of acid beta-glucosidase with pharmacological chaperone provides insight into Gaucher disease., Lieberman RL, Wustman BA, Huertas P, Powe AC Jr, Pine CW, Khanna R, Schlossmacher MG, Ringe D, Petsko GA, Nat Chem Biol. 2007 Feb;3(2):101-7. Epub 2006 Dec 24. PMID:17187079

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

About this StructureAbout this Structure

2nsx is a 4 chain structure of Acid-beta-glucosidase with sequence from Homo sapiens. Full crystallographic information is available from OCA.

See AlsoSee Also

• Acid-beta-glucosidase
• Treatment of Gaucher disease