3S5Z

Pharmacological Chaperoning in Human alpha-Galactosidase

Summary for 3S5Z

• Entry DOI: 10.2210/pdb3s5z/pdb
• Related: 1R46 1R47 3HG2 3HG3 3HG4 3HG5 3S5Y
• Descriptor: Alpha-galactosidase A, beta-D-xylopyranose-(1-2)-[alpha-D-mannopyranose-(1-3)][alpha-D-mannopyranose-(1-6)]beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-[alpha-L-fucopyranose-(1-3)]2-acetamido-2-deoxy-beta-D-glucopyranose, alpha-L-fucopyranose-(1-3)-[2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)]2-acetamido-2-deoxy-beta-D-glucopyranose, ... (10 entities in total)
• Functional Keywords: glycoprotein, carbohydrate-binding protein, glycosidase, lysosomal enzyme, (beta/alpha)8 barrel, pharmacological chaperone, hydrolase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 95196.11

Authors

Guce, A.I.,Clark, N.E.,Garman, S.C. (deposition date: 2011-05-23, release date: 2012-01-04, Last modification date: 2023-09-13)

Primary citation

Guce, A.I.,Clark, N.E.,Rogich, J.J.,Garman, S.C.
The molecular basis of pharmacological chaperoning in human alpha-galactosidase
Chem.Biol., 18:1521-1526, 2011

PubMed Abstract: Fabry disease patients show a deficiency in the activity of the lysosomal enzyme α-galactosidase (α-GAL or α-Gal A). One proposed treatment for Fabry disease is pharmacological chaperone therapy, where a small molecule stabilizes the α-GAL protein, leading to increased enzymatic activity. Using enzyme kinetics, tryptophan fluorescence, circular dichroism, and proteolysis assays, we show that the pharmacological chaperones 1-deoxygalactonojirimycin (DGJ) and galactose stabilize the human α-GAL glycoprotein. Crystal structures of complexes of α-GAL and chaperones explain the molecular basis for the higher potency of DGJ over galactose. Using site-directed mutagenesis, we show the higher potency of DGJ results from an ionic interaction with D170. We propose that protonation of D170 in acidic conditions leads to weaker binding of DGJ. The results establish a biochemical basis for pharmacological chaperone therapy applicable to other protein misfolding diseases.

PubMed: 22195554
DOI: 10.1016/j.chembiol.2011.10.012

Experimental method

X-RAY DIFFRACTION (2.001 Å)