4do6: Difference between revisions
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==Pharmacological chaperones for human alpha-N-acetylgalactosaminidase== | |||
=== | <StructureSection load='4do6' size='340' side='right' caption='[[4do6]], [[Resolution|resolution]] 1.60Å' scene=''> | ||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[4do6]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4DO6 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4DO6 FirstGlance]. <br> | |||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=2PE:NONAETHYLENE+GLYCOL'>2PE</scene>, <scene name='pdbligand=BGC:BETA-D-GLUCOSE'>BGC</scene>, <scene name='pdbligand=BMA:BETA-D-MANNOSE'>BMA</scene>, <scene name='pdbligand=CIT:CITRIC+ACID'>CIT</scene>, <scene name='pdbligand=GLC:ALPHA-D-GLUCOSE'>GLC</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=FUC:ALPHA-L-FUCOSE'>FUC</scene>, <scene name='pdbligand=MAN:ALPHA-D-MANNOSE'>MAN</scene></td></tr> | |||
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3h53|3h53]], [[3h54|3h54]], [[3h55|3h55]], [[3igu|3igu]], [[4do4|4do4]], [[4do5|4do5]]</td></tr> | |||
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">NAGA ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])</td></tr> | |||
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Alpha-N-acetylgalactosaminidase Alpha-N-acetylgalactosaminidase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.2.1.49 3.2.1.49] </span></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4do6 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4do6 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4do6 RCSB], [http://www.ebi.ac.uk/pdbsum/4do6 PDBsum]</span></td></tr> | |||
</table> | |||
== Disease == | |||
[[http://www.uniprot.org/uniprot/NAGAB_HUMAN NAGAB_HUMAN]] Defects in NAGA are the cause of Schindler disease (SCHIND) [MIM:[http://omim.org/entry/609241 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.<ref>PMID:2243144</ref> <ref>PMID:8782044</ref> Defects in NAGA are the cause of Kanzaki disease (KANZD) [MIM:[http://omim.org/entry/609242 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.<ref>PMID:8040340</ref> <ref>PMID:11251574</ref> | |||
== Function == | |||
[[http://www.uniprot.org/uniprot/NAGAB_HUMAN NAGAB_HUMAN]] Removes terminal alpha-N-acetylgalactosamine residues from glycolipids and glycopeptides. Required for the breakdown of glycolipids.<ref>PMID:9741689</ref> | |||
<div style="background-color:#fffaf0;"> | |||
== 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<ref>PMID:23045655</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
== References == | |||
== | <references/> | ||
__TOC__ | |||
</StructureSection> | |||
<references | |||
[[Category: Alpha-N-acetylgalactosaminidase]] | [[Category: Alpha-N-acetylgalactosaminidase]] | ||
[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: Clark, N E | [[Category: Clark, N E]] | ||
[[Category: Garman, S C | [[Category: Garman, S C]] | ||
[[Category: Carbohydrate-binding protein]] | [[Category: Carbohydrate-binding protein]] | ||
[[Category: Glycoprotein]] | [[Category: Glycoprotein]] | ||