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== Function == | == Function == | ||
[https://www.uniprot.org/uniprot/AGAL_HUMAN AGAL_HUMAN] | [https://www.uniprot.org/uniprot/AGAL_HUMAN AGAL_HUMAN] | ||
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== Publication Abstract from PubMed == | |||
Fabry disease patients show a deficiency in the activity of the lysosomal enzyme alpha-galactosidase (alpha-GAL or alpha-Gal A). One proposed treatment for Fabry disease is pharmacological chaperone therapy, where a small molecule stabilizes the alpha-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 alpha-GAL glycoprotein. Crystal structures of complexes of alpha-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. | |||
The Molecular Basis of Pharmacological Chaperoning in Human alpha-Galactosidase.,Guce AI, Clark NE, Rogich JJ, Garman SC Chem Biol. 2011 Dec 23;18(12):1521-6. PMID:22195554<ref>PMID:22195554</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
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==See Also== | ==See Also== | ||