4DO6

Pharmacological chaperones for human alpha-N-acetylgalactosaminidase

4DO6 の概要

• エントリーDOI: 10.2210/pdb4do6/pdb
• 関連するPDBエントリー: 3H53 3H54 3H55 3IGU 4DO4 4DO5
• 分子名称: Alpha-N-acetylgalactosaminidase, beta-D-mannopyranose-(1-4)-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)]beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, ... (10 entities in total)
• 機能のキーワード: beta/alpha)8 barrel, glycosidase, carbohydrate-binding protein, glycoprotein, lysosome, hydrolase
• 由来する生物種: Homo sapiens
• 細胞内の位置: Lysosome: P17050
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 96328.60

構造登録者

Clark, N.E.,Garman, S.C. (登録日: 2012-02-09, 公開日: 2012-10-10, 最終更新日: 2024-10-30)

主引用文献

Clark, N.E.,Metcalf, M.C.,Best, D.,Fleet, G.W.,Garman, S.C.
Pharmacological chaperones for human alpha-N-acetylgalactosaminidase
Proc.Natl.Acad.Sci.USA, 109:17400-17405, 2012

PubMed Abstract: Schindler/Kanzaki disease is an inherited metabolic disease with no current treatment options. This neurologic disease results from a defect in the lysosomal α-N-acetylgalactosaminidase (α-NAGAL) enzyme. In this report, we show evidence that the iminosugar DGJNAc can inhibit, stabilize, and chaperone human α-NAGAL both in vitro and in vivo. We demonstrate that a related iminosugar DGJ (currently in phase III clinical trials for another metabolic disorder, Fabry disease) can also chaperone human α-NAGAL in Schindler/Kanzaki disease. The 1.4- and 1.5-Å crystal structures of human α-NAGAL complexes reveal the different binding modes of iminosugars compared with glycosides. We show how differences in two functional groups result in >9 kcal/mol of additional binding energy and explain the molecular interactions responsible for the unexpectedly high affinity of the pharmacological chaperones. These results open two avenues for treatment of Schindler/Kanzaki disease and elucidate the atomic basis for pharmacological chaperoning in the entire family of lysosomal storage diseases.

PubMed: 23045655
DOI: 10.1073/pnas.1203924109

実験手法

X-RAY DIFFRACTION (1.6 Å)