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| | <StructureSection load='4ufh' size='340' side='right'caption='[[4ufh]], [[Resolution|resolution]] 2.16Å' scene=''> | | <StructureSection load='4ufh' size='340' side='right'caption='[[4ufh]], [[Resolution|resolution]] 2.16Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4ufh]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Lk3_transgenic_mice Lk3 transgenic mice]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4UFH OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4UFH FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4ufh]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4UFH OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4UFH FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=GIF:D-GALACTO-ISOFAGOMINE'>GIF</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=NI:NICKEL+(II)+ION'>NI</scene>, <scene name='pdbligand=PG4:TETRAETHYLENE+GLYCOL'>PG4</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.16Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4ufi|4ufi]], [[4ufj|4ufj]], [[4ufk|4ufk]], [[4ufl|4ufl]], [[4ufm|4ufm]]</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=GIF:D-GALACTO-ISOFAGOMINE'>GIF</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=NI:NICKEL+(II)+ION'>NI</scene>, <scene name='pdbligand=PG4:TETRAETHYLENE+GLYCOL'>PG4</scene></td></tr> |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Galactosylceramidase Galactosylceramidase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.2.1.46 3.2.1.46] </span></td></tr>
| + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4ufh FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4ufh OCA], [https://pdbe.org/4ufh PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4ufh RCSB], [https://www.ebi.ac.uk/pdbsum/4ufh PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4ufh ProSAT]</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=4ufh FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4ufh OCA], [http://pdbe.org/4ufh PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4ufh RCSB], [http://www.ebi.ac.uk/pdbsum/4ufh PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4ufh ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Disease == | | == Disease == |
| - | [[http://www.uniprot.org/uniprot/GALC_MOUSE GALC_MOUSE]] Defects in Galc are the cause of the 'twitcher' phenotype; an autosomal recessive leukodystrophy similar to the human disease (Krabbe disease). This deficiency results in the insufficient catabolism of several galactolipids that are important in the production of normal myelin. | + | [https://www.uniprot.org/uniprot/GALC_MOUSE GALC_MOUSE] Defects in Galc are the cause of the 'twitcher' phenotype; an autosomal recessive leukodystrophy similar to the human disease (Krabbe disease). This deficiency results in the insufficient catabolism of several galactolipids that are important in the production of normal myelin. |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/GALC_MOUSE GALC_MOUSE]] Hydrolyzes the galactose ester bonds of galactosylceramide, galactosylsphingosine, lactosylceramide, and monogalactosyldiglyceride. Enzyme with very low activity responsible for the lysosomal catabolism of galactosylceramide, a major lipid in myelin, kidney and epithelial cells of small intestine and colon.<ref>PMID:8769874</ref> | + | [https://www.uniprot.org/uniprot/GALC_MOUSE GALC_MOUSE] Hydrolyzes the galactose ester bonds of galactosylceramide, galactosylsphingosine, lactosylceramide, and monogalactosyldiglyceride. Enzyme with very low activity responsible for the lysosomal catabolism of galactosylceramide, a major lipid in myelin, kidney and epithelial cells of small intestine and colon.<ref>PMID:8769874</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Galactosylceramidase]] | |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Lk3 transgenic mice]] | + | [[Category: Mus musculus]] |
| - | [[Category: Christensen, S H]] | + | [[Category: Christensen SH]] |
| - | [[Category: Deane, J E]] | + | [[Category: Deane JE]] |
| - | [[Category: Hill, C H]] | + | [[Category: Hill CH]] |
| - | [[Category: Jensen, H H]] | + | [[Category: Jensen HH]] |
| - | [[Category: Moriarty, N W]] | + | [[Category: Moriarty NW]] |
| - | [[Category: Read, R J]] | + | [[Category: Read RJ]] |
| - | [[Category: Salamone, S]] | + | [[Category: Salamone S]] |
| - | [[Category: Spratley, S J]] | + | [[Category: Spratley SJ]] |
| - | [[Category: Viuff, A H]] | + | [[Category: Viuff AH]] |
| - | [[Category: Complex]]
| + | |
| - | [[Category: Glycosyl hydrolase]]
| + | |
| - | [[Category: Hydrolase]]
| + | |
| - | [[Category: Lysosome]]
| + | |
| Structural highlights
4ufh is a 1 chain structure with sequence from Mus musculus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Method: | X-ray diffraction, Resolution 2.16Å |
| Ligands: | , , , , |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Disease
GALC_MOUSE Defects in Galc are the cause of the 'twitcher' phenotype; an autosomal recessive leukodystrophy similar to the human disease (Krabbe disease). This deficiency results in the insufficient catabolism of several galactolipids that are important in the production of normal myelin.
Function
GALC_MOUSE Hydrolyzes the galactose ester bonds of galactosylceramide, galactosylsphingosine, lactosylceramide, and monogalactosyldiglyceride. Enzyme with very low activity responsible for the lysosomal catabolism of galactosylceramide, a major lipid in myelin, kidney and epithelial cells of small intestine and colon.[1]
Publication Abstract from PubMed
Krabbe disease is a devastating neurodegenerative disorder characterized by rapid demyelination of nerve fibers. This disease is caused by defects in the lysosomal enzyme beta-galactocerebrosidase (GALC), which hydrolyzes the terminal galactose from glycosphingolipids. These lipids are essential components of eukaryotic cell membranes: substrates of GALC include galactocerebroside, the primary lipid component of myelin, and psychosine, a cytotoxic metabolite. Mutations of GALC that cause misfolding of the protein may be responsive to pharmacological chaperone therapy (PCT), whereby small molecules are used to stabilize these mutant proteins, thus correcting trafficking defects and increasing residual catabolic activity in cells. Here we describe a new approach for the synthesis of galacto-configured azasugars and the characterization of their interaction with GALC using biophysical, biochemical and crystallographic methods. We identify that the global stabilization of GALC conferred by azasugar derivatives, measured by fluorescence-based thermal shift assays, is directly related to their binding affinity, measured by enzyme inhibition. X-ray crystal structures of these molecules bound in the GALC active site reveal which residues participate in stabilizing interactions, show how potency is achieved and illustrate the penalties of aza/iminosugar ring distortion. The structure-activity relationships described here identify the key physical properties required of pharmacological chaperones for Krabbe disease and highlight the potential of azasugars as stabilizing agents for future enzyme replacement therapies. This work lays the foundation for new drug-based treatments of Krabbe disease.
Azasugar inhibitors as pharmacological chaperones for Krabbe disease.,Hill CH, Viuff AH, Spratley SJ, Salamone S, Christensen SH, Read RJ, Moriarty NW, Jensen HH, Deane JE Chem Sci. 2015 May 20;6(5):3075-3086. Epub 2015 Mar 30. PMID:26029356[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Sakai N, Inui K, Tatsumi N, Fukushima H, Nishigaki T, Taniike M, Nishimoto J, Tsukamoto H, Yanagihara I, Ozono K, Okada S. Molecular cloning and expression of cDNA for murine galactocerebrosidase and mutation analysis of the twitcher mouse, a model of Krabbe's disease. J Neurochem. 1996 Mar;66(3):1118-24. PMID:8769874
- ↑ Hill CH, Viuff AH, Spratley SJ, Salamone S, Christensen SH, Read RJ, Moriarty NW, Jensen HH, Deane JE. Azasugar inhibitors as pharmacological chaperones for Krabbe disease. Chem Sci. 2015 May 20;6(5):3075-3086. Epub 2015 Mar 30. PMID:26029356 doi:http://dx.doi.org/10.1039/c5sc00754b
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