4do4

Pharmacological chaperones for human alpha-N-acetylgalactosaminidasePharmacological chaperones for human alpha-N-acetylgalactosaminidase

Structural highlights 4do4 is a 2 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: , , , , , , , Related: 3h53, 3h54, 3h55, 3igu, 4do5, 4do6 Gene: NAGA (HUMAN) Activity: Alpha-N-acetylgalactosaminidase, with EC number 3.2.1.49 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease [NAGAB_HUMAN] Defects in NAGA are the cause of Schindler disease (SCHIND) [MIM:609241]. Schindler disease is a form of NAGA deficiency characterized by early onset neuroaxonal dystrophy and neurological signs (convulsion during fever, epilepsy, psychomotor retardation and hypotonia). NAGA deficiency is typically classified in three main phenotypes: NAGA deficiency type I (Schindler disease or Schindler disease type I) with severe manifestations; NAGA deficiency type II (Kanzazi disease or Schindler disease type II) which is mild; NAGA deficiency type III (Schindler disease type III) characterized by mild-to-moderate neurologic manifestations. NAGA deficiency results in the increased urinary excretion of glycopeptides and oligosaccharides containing alpha-N-acetylgalactosaminyl moieties. Inheritance is autosomal recessive. Defects in NAGA are the cause of Kanzaki disease (KANZD) [MIM:609242]; also known as NAGA deficiency type II or Schindler disease type II. Kanzaki disease is an autosomal recessive disorder characterized by late onset, angiokeratoma corporis diffusum and mild intellectual impairment. Function [NAGAB_HUMAN] Removes terminal alpha-N-acetylgalactosamine residues from glycolipids and glycopeptides. Required for the breakdown of glycolipids. Publication Abstract from PubMed Schindler/Kanzaki disease is an inherited metabolic disease with no current treatment options. This neurologic disease results from a defect in the lysosomal alpha-N-acetylgalactosaminidase (alpha-NAGAL) enzyme. In this report, we show evidence that the iminosugar DGJNAc can inhibit, stabilize, and chaperone human alpha-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 alpha-NAGAL in Schindler/Kanzaki disease. The 1.4- and 1.5-A crystal structures of human alpha-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. Pharmacological chaperones for human alpha-N-acetylgalactosaminidase.,Clark NE, Metcalf MC, Best D, Fleet GW, Garman SC Proc Natl Acad Sci U S A. 2012 Oct 23;109(43):17400-5. doi:, 10.1073/pnas.1203924109. Epub 2012 Oct 8. PMID:23045655 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

spinqualitylabelsall models 4do4, resolution 1.40Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image