1OGS

human acid-beta-glucosidase

Summary for 1OGS

• Entry DOI: 10.2210/pdb1ogs/pdb
• Descriptor: Glucosylceramidase, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, SULFATE ION, ... (5 entities in total)
• Functional Keywords: hydrolase, gaucher disease, glucosidase, glucocerebrosidase, cerezyme hydrolase, glycosidase, sphingolipid metabolism, glycoprote lysosome, membrane, disease mutati polymorphism, alternative initiation, pharmaceutical, israel structural proteomics center, ispc, structural genomics
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 113366.89

Authors

Dvir, H.,Harel, M.,McCarthy, A.A.,Toker, L.,Silman, I.,Futerman, A.H.,Sussman, J.L. (deposition date: 2003-05-13, release date: 2003-07-03, Last modification date: 2024-11-20)

Primary citation

Dvir, H.,Harel, M.,Mccarthy, A.A.,Toker, L.,Silman, I.,Futerman, A.H.,Sussman, J.L.
X-Ray Structure of Human Acid-Beta-Glucosidase, the Defective Enzyme in Gaucher Disease
Embo Rep., 4:704-, 2003

PubMed Abstract: Gaucher disease, the most common lysosomal storage disease, is caused by mutations in the gene that encodes acid-beta-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 approximately 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 A resolution. The catalytic domain consists of a (beta/alpha)(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 alpha-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.

PubMed: 12792654
DOI: 10.1038/SJ.EMBOR.EMBOR873

Experimental method

X-RAY DIFFRACTION (2 Å)