1R47

Structure of human alpha-galactosidase

Summary for 1R47

• Entry DOI: 10.2210/pdb1r47/pdb
• Related: 1R46
• Descriptor: Alpha-galactosidase A, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, alpha-D-mannopyranose-(1-3)-[alpha-D-mannopyranose-(1-6)]alpha-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, ... (8 entities in total)
• Functional Keywords: glycoprotein, carbohydrate-binding protein, glycosidase, lysosomal enzyme, (beta/alpha)8 barrel, hydrolase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 95749.63

Authors

Garman, S.C.,Garboczi, D.N. (deposition date: 2003-10-03, release date: 2004-03-16, Last modification date: 2024-11-13)

Primary citation

Garman, S.C.,Garboczi, D.N.
The molecular defect leading to Fabry disease: structure of human alpha-galactosidase
J.Mol.Biol., 337:319-335, 2004

PubMed Abstract: Fabry disease is an X-linked lysosomal storage disease afflicting 1 in 40,000 males with chronic pain, vascular degeneration, cardiac impairment, and other symptoms. Deficiency in the lysosomal enzyme alpha-galactosidase (alpha-GAL) causes an accumulation of its substrate, which ultimately leads to Fabry disease symptoms. Here, we present the structure of the human alpha-GAL glycoprotein determined by X-ray crystallography. The structure is a homodimer with each monomer containing a (beta/alpha)8 domain with the active site and an antiparallel beta domain. N-linked carbohydrate appears at six sites in the glycoprotein dimer, revealing the basis for lysosomal transport via the mannose-6-phosphate receptor. To understand how the enzyme cleaves galactose from glycoproteins and glycolipids, we also determined the structure of the complex of alpha-GAL with its catalytic product. The catalytic mechanism of the enzyme is revealed by the location of two aspartic acid residues (D170 and D231), which act as a nucleophile and an acid/base, respectively. As a point mutation in alpha-GAL can lead to Fabry disease, we have catalogued and plotted the locations of 245 missense and nonsense mutations in the three-dimensional structure. The structure of human alpha-GAL brings Fabry disease into the realm of molecular diseases, where insights into the structural basis of the disease phenotypes might help guide the clinical treatment of patients.

PubMed: 15003450
DOI: 10.1016/j.jmb.2004.01.035

Experimental method

X-RAY DIFFRACTION (3.45 Å)