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| [[Image:2nt1.jpg|left|200px]] | | {{Seed}} |
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| {{STRUCTURE_2nt1| PDB=2nt1 | SCENE= }} | | {{STRUCTURE_2nt1| PDB=2nt1 | SCENE= }} |
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| '''Structure of acid-beta-glucosidase at neutral pH'''
| | ===Structure of acid-beta-glucosidase at neutral pH=== |
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| ==Overview==
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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.
| | The line below this paragraph, {{ABSTRACT_PUBMED_17187079}}, adds the Publication Abstract to the page |
| | (as it appears on PubMed at http://www.pubmed.gov), where 17187079 is the PubMed ID number. |
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| | {{ABSTRACT_PUBMED_17187079}} |
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| ==Disease== | | ==Disease== |
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| [[Category: Gaucher disease]] | | [[Category: Gaucher disease]] |
| [[Category: Glucosylceramide]] | | [[Category: Glucosylceramide]] |
| ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun May 4 09:52:42 2008'' | | |
| | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Tue Jul 29 11:28:32 2008'' |
