4DO6

Pharmacological chaperones for human alpha-N-acetylgalactosaminidase

Summary for 4DO6

• Entry DOI: 10.2210/pdb4do6/pdb
• Related: 3H53 3H54 3H55 3IGU 4DO4 4DO5
• Descriptor: 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)
• Functional Keywords: beta/alpha)8 barrel, glycosidase, carbohydrate-binding protein, glycoprotein, lysosome, hydrolase
• Biological source: Homo sapiens
• Cellular location: Lysosome: P17050
• Total number of polymer chains: 2
• Total formula weight: 96328.60

Authors

Clark, N.E.,Garman, S.C. (deposition date: 2012-02-09, release date: 2012-10-10, Last modification date: 2024-10-30)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (1.6 Å)