X-ray structure of human acid-beta-glucosidase covalently bound to conduritol-B-epoxide: Implications for Gaucher disease

Lakshmanane, Premkumar, Sawkar, Anu R., Boldin-Adamsky, Swetlana, Toker, Lilly, Silman, Israel, Kelly, Jeffery W., Futerman, Anthony H. and Sussman, Joel L. (2005) X-ray structure of human acid-beta-glucosidase covalently bound to conduritol-B-epoxide: Implications for Gaucher disease. Journal of Biological Chemistry, 280 25: 23815-23819. doi:10.1074/jbc.M502799200

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Author Lakshmanane, Premkumar
Sawkar, Anu R.
Boldin-Adamsky, Swetlana
Toker, Lilly
Silman, Israel
Kelly, Jeffery W.
Futerman, Anthony H.
Sussman, Joel L.
Title X-ray structure of human acid-beta-glucosidase covalently bound to conduritol-B-epoxide: Implications for Gaucher disease
Formatted title
X-ray structure of human acid-β-glucosidase covalently bound to conduritol-B-epoxide: Implications for Gaucher disease
Journal name Journal of Biological Chemistry   Check publisher's open access policy
ISSN 0021-9258
1083-351X
1067-8816
Publication date 2005-06-24
Sub-type Article (original research)
DOI 10.1074/jbc.M502799200
Open Access Status File (Publisher version)
Volume 280
Issue 25
Start page 23815
End page 23819
Total pages 5
Place of publication Bethesda, MD, U.S.A.
Publisher American Society for Biochemistry and Molecular Biology
Language eng
Formatted abstract
Gaucher disease is an inherited metabolic disorder caused by mutations in the lysosomal enzyme acid-β-glucosidase (GlcCerase). We recently determined the x-ray structure of GlcCerase to 2.0 Å resolution (Dvir, H., Harel, M., McCarthy, A. A., Toker, L., Silman, I., Futerman, A. H., and Sussman, J. L. (2003) EMBO Rep.4, 704–709) and have now solved the structure of Glc-Cerase conjugated with an irreversible inhibitor, conduritol-B-epoxide (CBE). The crystal structure reveals that binding of CBE to the active site does not induce a global conformational change in GlcCerase and confirms that Glu340 is the catalytic nucleophile. However, only one of two alternative conformations of a pair of flexible loops (residues 345–349 and 394–399) located at the entrance to the active site in native GlcCerase is observed in the GlcCerase-CBE structure, a conformation in which the active site is accessible to CBE. Analysis of the dynamics of these two alternative conformations suggests that the two loops act as a lid at the entrance to the active site. This possibility is supported by a cluster of mutations in loop 394–399 that cause Gaucher disease by reducing catalytic activity. Moreover, in silico mutational analysis demonstrates that all these mutations stabilize the conformation that limits access to the active site, thus providing a mechanistic explanation of how mutations in this loop result in Gaucher disease.
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collection: Institute for Molecular Bioscience - Publications
 
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Created: Tue, 06 Sep 2011, 20:22:45 EST by Susan Allen on behalf of Institute for Molecular Bioscience