SEARCH Journal home Press releases Aims and scope Authors and referees  Guide for authors  Guide for referees  Contact editors  Advisors & Advisory  Editorial Board  Submit a Manuscript Customer Services  Subscriptions  Order sample copy  Purchase articles  Reprints and   permissions  Contact NPG  Advertising www.embo.org EMBO reports 4, 7, 704–709 (2003) doi:10.1038/sj.embor.embor873 AOP Published online: 3 June 2003 X-ray structure of human acid--glucosidase, the defective enzyme in Gaucher disease Hay Dvir1, 2, Michal Harel1, Andrew A. McCarthy3, Lilly Toker2, Israel Silman2, Anthony H. Futerman4 & Joel L. Sussman1 1  Department of Structural Biology, Weizmann Institute of Science, Rehovot 76100, Israel 2  Department of Neurobiology, Weizmann Institute of Science, Rehovot 76100, Israel 3  EMBL Outstation, Grenoble, BP181, 38042, France 4  Department of Biological Chemistry, Weizmann Institute of Science, Rehovot 76100, Israel To whom correspondence should be addressed Anthony H. Futerman  Tel: +972 8 934 2704; Fax: +972 8 934 4112; tony.futerman@weizmann.ac.il Joel L. Sussman  Tel: +972 8 934 4531; Fax: +972 8 934 4159; joel.sussman@weizmann.ac.il Received 22 April 2003; Accepted 7 May 2003; Published online 3 June 2003. Abstract Gaucher disease, the most common lysosomal storage disease, is caused by mutations in the gene that encodes acid--glucosidase (GlcCerase). Type 1 is characterized by hepatosplenomegaly, and types 2 and 3 by early or chronic onset of severe neurological symptoms. No clear correlation exists between the 200 GlcCerase mutations and disease severity, although homozygosity for the common mutations N370S and L444P is associated with non- neuronopathic and neuronopathic disease, respectively. We report the X-ray structure of GlcCerase at 2.0 Å resolution. The catalytic domain consists of a (/)8 TIM barrel, as expected for a member of the glucosidase hydrolase A clan. The distance between the catalytic residues E235 and E340 is consistent with a catalytic mechanism of retention. N370 is located on the longest -helix (helix 7), which has several other mutations of residues that point into the TIM barrel. Helix 7 is at the interface between the TIM barrel and a separate immunoglobulin-like domain on which L444 is located, suggesting an important regulatory or structural role for this non-catalytic domain. The structure provides the possibility of engineering improved GlcCerase for enzyme-replacement therapy, and for designing structure-based drugs aimed at restoring the activity of defective GlcCerase. top  This article Email link to a friend Download PDF Full text Rights and permissions Reprints Privacy PolicyCopyright © 2003 by the European Molecular Biology Organization