3S5Y

Pharmacological Chaperoning in Human alpha-Galactosidase

3S5Y の概要

• エントリーDOI: 10.2210/pdb3s5y/pdb
• 関連するPDBエントリー: 1R46 1R47 3HG2 3HG3 3HG4 3HG5 3S5Z
• 分子名称: Alpha-galactosidase A, 1,2-ETHANEDIOL, ACETIC ACID, ... (12 entities in total)
• 機能のキーワード: glycoprotein, carbohydrate-binding protein, glycosidase, lysosomal enzyme, (beta/alpha)8 barrel, pharmacological chaperone, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 97829.15

構造登録者

Guce, A.I.,Clark, N.E.,Garman, S.C. (登録日: 2011-05-23, 公開日: 2012-01-04, 最終更新日: 2024-10-30)

主引用文献

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

実験手法

X-RAY DIFFRACTION (2.105 Å)