2v3d: Difference between revisions
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==ACID-BETA-GLUCOSIDASE WITH N-BUTYL-DEOXYNOJIRIMYCIN== | |||
=== | <StructureSection load='2v3d' size='340' side='right' caption='[[2v3d]], [[Resolution|resolution]] 1.96Å' scene=''> | ||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[2v3d]] 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=2V3D OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2V3D FirstGlance]. <br> | |||
</td></tr><tr><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=BMA:BETA-D-MANNOSE'>BMA</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=NBV:(2R,3R,4R,5S)-1-BUTYL-2-(HYDROXYMETHYL)PIPERIDINE-3,4,5-TRIOL'>NBV</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=FUC:ALPHA-L-FUCOSE'>FUC</scene><br> | |||
<tr><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1ogs|1ogs]], [[1y7v|1y7v]], [[2f61|2f61]], [[2j25|2j25]], [[2v3e|2v3e]], [[2v3f|2v3f]]</td></tr> | |||
<tr><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Glucosylceramidase Glucosylceramidase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.2.1.45 3.2.1.45] </span></td></tr> | |||
<tr><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2v3d FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2v3d OCA], [http://www.rcsb.org/pdb/explore.do?structureId=2v3d RCSB], [http://www.ebi.ac.uk/pdbsum/2v3d PDBsum]</span></td></tr> | |||
<table> | |||
== Evolutionary Conservation == | |||
[[Image:Consurf_key_small.gif|200px|right]] | |||
Check<jmol> | |||
<jmolCheckbox> | |||
<scriptWhenChecked>select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/v3/2v3d_consurf.spt"</scriptWhenChecked> | |||
<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked> | |||
<text>to colour the structure by Evolutionary Conservation</text> | |||
</jmolCheckbox> | |||
</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/chain_selection.php?pdb_ID=2ata ConSurf]. | |||
<div style="clear:both"></div> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Gaucher disease is caused by mutations in the gene encoding acid beta-glucosidase (GlcCerase), resulting in glucosylceramide (GlcCer) accumulation. The only currently available orally administered treatment for Gaucher disease is N-butyl-deoxynojirimycin (Zavesca, NB-DNJ), which partially inhibits GlcCer synthesis, thus reducing levels of GlcCer accumulation. NB-DNJ also acts as a chemical chaperone for GlcCerase, although at a different concentration than that required to completely inhibit GlcCer synthesis. We now report the crystal structures, at 2A resolution, of complexes of NB-DNJ and N-nonyl-deoxynojirimycin (NN-DNJ) with recombinant human GlcCerase, expressed in cultured plant cells. Both inhibitors bind at the active site of GlcCerase, with the imino sugar moiety making hydrogen bonds to side chains of active site residues. The alkyl chains of NB-DNJ and NN-DNJ are oriented toward the entrance of the active site where they undergo hydrophobic interactions. Based on these structures, we make a number of predictions concerning (i) involvement of loops adjacent to the active site in the catalytic process, (ii) the nature of nucleophilic attack by Glu-340, and (iii) the role of a conserved water molecule located in a solvent cavity adjacent to the active site. Together, these results have significance for understanding the mechanism of action of GlcCerase and the mode of GlcCerase chaperoning by imino sugars. | |||
Crystal structures of complexes of N-butyl- and N-nonyl-deoxynojirimycin bound to acid beta-glucosidase: insights into the mechanism of chemical chaperone action in Gaucher disease.,Brumshtein B, Greenblatt HM, Butters TD, Shaaltiel Y, Aviezer D, Silman I, Futerman AH, Sussman JL J Biol Chem. 2007 Sep 28;282(39):29052-8. Epub 2007 Jul 31. PMID:17666401<ref>PMID:17666401</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
==See Also== | ==See Also== | ||
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*[[Treatment of Gaucher disease|Treatment of Gaucher disease]] | *[[Treatment of Gaucher disease|Treatment of Gaucher disease]] | ||
*[[User:Boris Brumshtein|User:Boris Brumshtein]] | *[[User:Boris Brumshtein|User:Boris Brumshtein]] | ||
== References == | |||
== | <references/> | ||
__TOC__ | |||
</StructureSection> | |||
[[Category: Glucosylceramidase]] | [[Category: Glucosylceramidase]] | ||
[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
Revision as of 04:33, 1 October 2014
ACID-BETA-GLUCOSIDASE WITH N-BUTYL-DEOXYNOJIRIMYCINACID-BETA-GLUCOSIDASE WITH N-BUTYL-DEOXYNOJIRIMYCIN
Structural highlights
Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMedGaucher disease is caused by mutations in the gene encoding acid beta-glucosidase (GlcCerase), resulting in glucosylceramide (GlcCer) accumulation. The only currently available orally administered treatment for Gaucher disease is N-butyl-deoxynojirimycin (Zavesca, NB-DNJ), which partially inhibits GlcCer synthesis, thus reducing levels of GlcCer accumulation. NB-DNJ also acts as a chemical chaperone for GlcCerase, although at a different concentration than that required to completely inhibit GlcCer synthesis. We now report the crystal structures, at 2A resolution, of complexes of NB-DNJ and N-nonyl-deoxynojirimycin (NN-DNJ) with recombinant human GlcCerase, expressed in cultured plant cells. Both inhibitors bind at the active site of GlcCerase, with the imino sugar moiety making hydrogen bonds to side chains of active site residues. The alkyl chains of NB-DNJ and NN-DNJ are oriented toward the entrance of the active site where they undergo hydrophobic interactions. Based on these structures, we make a number of predictions concerning (i) involvement of loops adjacent to the active site in the catalytic process, (ii) the nature of nucleophilic attack by Glu-340, and (iii) the role of a conserved water molecule located in a solvent cavity adjacent to the active site. Together, these results have significance for understanding the mechanism of action of GlcCerase and the mode of GlcCerase chaperoning by imino sugars. Crystal structures of complexes of N-butyl- and N-nonyl-deoxynojirimycin bound to acid beta-glucosidase: insights into the mechanism of chemical chaperone action in Gaucher disease.,Brumshtein B, Greenblatt HM, Butters TD, Shaaltiel Y, Aviezer D, Silman I, Futerman AH, Sussman JL J Biol Chem. 2007 Sep 28;282(39):29052-8. Epub 2007 Jul 31. PMID:17666401[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also
References
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Proteopedia Page Contributors and Editors (what is this?)Proteopedia Page Contributors and Editors (what is this?)
OCA- Glucosylceramidase
- Homo sapiens
- Aviezer, D.
- Brumshtein, B.
- Butters, T D.
- Futerman, A H.
- Greenblatt, H M.
- Shaaltiel, Y.
- Silman, I.
- Sussman, J L.
- Acid-beta-glucosidase
- Disease mutation
- Gaucher disease
- Glycoprotein
- Glycosidase
- Hydrolase
- Lipid metabolism
- Lysosome
- Membrane
- N-butyl-deoxynojirimycin
- N-butyl-deoxynojirimycinalternative initiation
- Sphingolipid metabolism