We found a match
Your institution may have access to this item. Find your institution then sign in to continue.
- Title
X-ray structure of human acid-ß-glucosidase, the defective enzyme in Gaucher disease.
- Authors
Dvir, Hay; Harel, Michal; Mccarthy, Andrew A.; Toker, Lilly; Silman, Israel; Futerman, Anthony H.; Sussman, Joel L.
- Abstract
Gaucher disease, the most common lysosomal storage disease, is caused by mutations in the gene that encodes acid-β-glucosidase (GlcCerase). Type 1 is characterized by hepatosplenomegaly, and types 2 and 3 by early or chronic onset of severe neuronoathic disease, respectively. We report the X-ray structure of GlcCerase at 20 Å resolution. The catalytic domain consists of a(β/α)B 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 α-helix (helix7), 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.
- Subjects
GLUCOSIDASES; ENZYMES; LYSOSOMAL storage diseases; GENETIC mutation; IMMUNOGLOBULINS; HYDROLASES
- Publication
EMBO Reports, 2003, Vol 4, Issue 7, p704
- ISSN
1469-221X
- Publication type
Article
- DOI
10.1038/sj.embor.embor873