1R47: Structure of Human Alpha-galactosidase

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.
PDB ID: 1R47Download
MMDB ID: 26893
PDB Deposition Date: 2003/10/3
Updated in MMDB: 2012/12 
Experimental Method:
x-ray diffraction
Resolution: 3.45  Å
Source Organism:
Similar Structures:
Biological Unit for 1R47: dimeric; determined by author and by software (PISA)
Molecular Components in 1R47
Label Count Molecule
Proteins (2 molecules)
Alpha-galactosidase a
(Gene: GLA)
Molecule annotation
Chemicals (28 molecules)
* Click molecule labels to explore molecular sequence information.

Citing MMDB