Letter abstract
Nature Chemical Biology 3, 101 - 107 (2006)
Published online: 24 December 2006 | doi:10.1038/nchembio850
Structure of acid 
-glucosidase with pharmacological chaperone provides insight into Gaucher disease
Raquel L Lieberman1,2,3, Brandon A Wustman4, Pedro Huertas4,5, Allan C Powe, Jr4, Corey W Pine4, Richie Khanna4, Michael G Schlossmacher2, Dagmar Ringe1,2,3 & Gregory A Petsko1,2,3
Gaucher disease results from mutations in the lysosomal enzyme acid 
-glucosidase (GCase)1. 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 GCase2. 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.
- Structural Neurology Lab at the Brigham and Women's Hospital and Harvard Medical School, 77 Ave Louis Pasteur, Boston, Massachusetts 02115, USA
- Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, 77 Ave Louis Pasteur, Boston, Massachusetts 02115, USA.
- Rosenstiel Center for Basic Biomedical Sciences, Brandeis University, 415 South Street, Waltham, Massachusetts 02454, USA.
- Amicus Therapeutics, 6 Cedar Brook Drive, Cranbury, New Jersey 08512, USA.
- The Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Building E25-519, 71 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA.
Correspondence to: Gregory A Petsko1,2,3 e-mail: petsko@brandeis.edu
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