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2v3d

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{{STRUCTURE_2v3d| PDB=2v3d | SCENE= }}
 
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===ACID-BETA-GLUCOSIDASE WITH N-BUTYL-DEOXYNOJIRIMYCIN===
 
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{{ABSTRACT_PUBMED_17666401}}
 
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==About this Structure==
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==acid-beta-glucosidase with N-butyl-deoxynojirimycin==
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[[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].
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<StructureSection load='2v3d' size='340' side='right'caption='[[2v3d]], [[Resolution|resolution]] 1.96&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[2v3d]] is a 2 chain structure with sequence from [https://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 [https://proteopedia.org/fgij/fg.htm?mol=2V3D FirstGlance]. <br>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.96&#8491;</td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=BMA:BETA-D-MANNOSE'>BMA</scene>, <scene name='pdbligand=FUC:ALPHA-L-FUCOSE'>FUC</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></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=2v3d FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2v3d OCA], [https://pdbe.org/2v3d PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2v3d RCSB], [https://www.ebi.ac.uk/pdbsum/2v3d PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2v3d ProSAT]</span></td></tr>
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</table>
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== Disease ==
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[https://www.uniprot.org/uniprot/GLCM_HUMAN GLCM_HUMAN] Defects in GBA are the cause of Gaucher disease (GD) [MIM:[https://omim.org/entry/230800 230800]; also known as glucocerebrosidase deficiency. GD is the most prevalent lysosomal storage disease, characterized by accumulation of glucosylceramide in the reticulo-endothelial system. Different clinical forms are recognized depending on the presence (neuronopathic forms) or absence of central nervous system involvement, severity and age of onset.<ref>PMID:8294033</ref> [:]<ref>PMID:19286695</ref> <ref>PMID:16293621</ref> <ref>PMID:1974409</ref> <ref>PMID:1972019</ref> <ref>PMID:8432537</ref> <ref>PMID:7916532</ref> <ref>PMID:8112750</ref> <ref>PMID:8076951</ref> <ref>PMID:8790604</ref> <ref>PMID:7627184</ref> <ref>PMID:7627192</ref> <ref>PMID:8937765</ref> <ref>PMID:8829654</ref> <ref>PMID:8829663</ref> <ref>PMID:8889591</ref> <ref>PMID:8780099</ref> <ref>PMID:9182788</ref> <ref>PMID:9217217</ref> <ref>PMID:9279145</ref> <ref>PMID:9153297</ref> <ref>PMID:9061570</ref> <ref>PMID:9554454</ref> <ref>PMID:9683600</ref> <ref>PMID:9637431</ref> <ref>PMID:9516376</ref> <ref>PMID:9851895</ref> <ref>PMID:9650766</ref> <ref>PMID:9554746</ref> <ref>PMID:10206680</ref> <ref>PMID:10340647</ref> <ref>PMID:10360404</ref> <ref>PMID:10744424</ref> <ref>PMID:10352942</ref> <ref>PMID:10447266</ref> <ref>PMID:10796875</ref> <ref>PMID:11992489</ref> <ref>PMID:11933202</ref> <ref>PMID:12204005</ref> <ref>PMID:12847165</ref> <ref>PMID:15292921</ref> <ref>PMID:15826241</ref> <ref>PMID:15605411</ref> <ref>PMID:16148263</ref> <ref>PMID:17620502</ref> <ref>PMID:18332251</ref> <ref>PMID:19846850</ref> Defects in GBA are the cause of Gaucher disease type 1 (GD1) [MIM:[https://omim.org/entry/230800 230800]; also known as adult non-neuronopathic Gaucher disease. GD1 is characterized by hepatosplenomegaly with consequent anemia and thrombopenia, and bone involvement. The central nervous system is not involved.[:]<ref>PMID:19286695</ref> <ref>PMID:8889591</ref> <ref>PMID:10206680</ref> <ref>PMID:10340647</ref> <ref>PMID:12847165</ref> <ref>PMID:15605411</ref> <ref>PMID:16148263</ref> <ref>PMID:17620502</ref> <ref>PMID:18332251</ref> <ref>PMID:19846850</ref> Defects in GBA are the cause of Gaucher disease type 2 (GD2) [MIM:[https://omim.org/entry/230900 230900]; also known as acute neuronopathic Gaucher disease. GD2 is the most severe form and is universally progressive and fatal. It manifests soon after birth, with death generally occurring before patients reach two years of age.<ref>PMID:19286695</ref> <ref>PMID:9637431</ref> <ref>PMID:9851895</ref> <ref>PMID:12847165</ref> <ref>PMID:16148263</ref> <ref>PMID:17620502</ref> <ref>PMID:18332251</ref> <ref>PMID:19846850</ref> Defects in GBA are the cause of Gaucher disease type 3 (GD3) [MIM:[https://omim.org/entry/231000 231000]; also known as subacute neuronopathic Gaucher disease. GD3 has central nervous manifestations.<ref>PMID:19286695</ref> <ref>PMID:8780099</ref> <ref>PMID:12847165</ref> <ref>PMID:16148263</ref> <ref>PMID:17620502</ref> <ref>PMID:18332251</ref> <ref>PMID:19846850</ref> Defects in GBA are the cause of Gaucher disease type 3C (GD3C) [MIM:[https://omim.org/entry/231005 231005]; also known as pseudo-Gaucher disease or Gaucher-like disease.<ref>PMID:19286695</ref> <ref>PMID:12847165</ref> <ref>PMID:16148263</ref> <ref>PMID:17620502</ref> <ref>PMID:18332251</ref> <ref>PMID:19846850</ref> Defects in GBA are the cause of Gaucher disease perinatal lethal (GDPL) [MIM:[https://omim.org/entry/608013 608013]. It is a distinct form of Gaucher disease type 2, characterized by fetal onset. Hydrops fetalis, in utero fetal death and neonatal distress are prominent features. When hydrops is absent, neurologic involvement begins in the first week and leads to death within 3 months. Hepatosplenomegaly is a major sign, and is associated with ichthyosis, arthrogryposis, and facial dysmorphism.<ref>PMID:19286695</ref> <ref>PMID:12847165</ref> <ref>PMID:16148263</ref> <ref>PMID:17620502</ref> <ref>PMID:18332251</ref> <ref>PMID:19846850</ref> Note=Perinatal lethal Gaucher disease is associated with non-immune hydrops fetalis, a generalized edema of the fetus with fluid accumulation in the body cavities due to non-immune causes. Non-immune hydrops fetalis is not a diagnosis in itself but a symptom, a feature of many genetic disorders, and the end-stage of a wide variety of disorders.<ref>PMID:19286695</ref> <ref>PMID:12847165</ref> <ref>PMID:16148263</ref> <ref>PMID:17620502</ref> <ref>PMID:18332251</ref> <ref>PMID:19846850</ref> Defects in GBA contribute to susceptibility to Parkinson disease (PARK) [MIM:[https://omim.org/entry/168600 168600]. A complex neurodegenerative disorder characterized by bradykinesia, resting tremor, muscular rigidity and postural instability. Additional features are characteristic postural abnormalities, dysautonomia, dystonic cramps, and dementia. The pathology of Parkinson disease involves the loss of dopaminergic neurons in the substantia nigra and the presence of Lewy bodies (intraneuronal accumulations of aggregated proteins), in surviving neurons in various areas of the brain. The disease is progressive and usually manifests after the age of 50 years, although early-onset cases (before 50 years) are known. The majority of the cases are sporadic suggesting a multifactorial etiology based on environmental and genetic factors. However, some patients present with a positive family history for the disease. Familial forms of the disease usually begin at earlier ages and are associated with atypical clinical features.<ref>PMID:19286695</ref> <ref>PMID:12847165</ref> <ref>PMID:16148263</ref> <ref>PMID:17620502</ref> <ref>PMID:18332251</ref> <ref>PMID:19846850</ref>
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== Function ==
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[https://www.uniprot.org/uniprot/GLCM_HUMAN GLCM_HUMAN]
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== Evolutionary Conservation ==
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[[Image:Consurf_key_small.gif|200px|right]]
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Check<jmol>
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<jmolCheckbox>
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<scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/v3/2v3d_consurf.spt"</scriptWhenChecked>
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<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
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<text>to colour the structure by Evolutionary Conservation</text>
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</jmolCheckbox>
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</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/main_output.php?pdb_ID=2v3d ConSurf].
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<div style="clear:both"></div>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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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.
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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>
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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</div>
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<div class="pdbe-citations 2v3d" style="background-color:#fffaf0;"></div>
==See Also==
==See Also==
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*[[Acid beta-glucosidase with N-butyl-deoxynojirimycin|Acid beta-glucosidase with N-butyl-deoxynojirimycin]]
 
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*[[Acid beta-glucosidase with N-nonyl-deoxynojirimycin|Acid beta-glucosidase with N-nonyl-deoxynojirimycin]]
 
*[[Acid-beta-glucosidase|Acid-beta-glucosidase]]
*[[Acid-beta-glucosidase|Acid-beta-glucosidase]]
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*[[Hemagglutinin|Hemagglutinin]]
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*[[Acid-beta-glucosidase 3D structures|Acid-beta-glucosidase 3D structures]]
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*[[IFG/DG-Cerezyme|IFG/DG-Cerezyme]]
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*[[Beta-glucosidase|Beta-glucosidase]]
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*[[Treatment of Gaucher disease|Treatment of Gaucher disease]]
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== References ==
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*[[User:Boris Brumshtein|User:Boris Brumshtein]]
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<references/>
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__TOC__
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==Reference==
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</StructureSection>
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<ref group="xtra">PMID:017666401</ref><references group="xtra"/><references/>
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[[Category: Glucosylceramidase]]
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[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
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[[Category: Aviezer, D.]]
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[[Category: Large Structures]]
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[[Category: Brumshtein, B.]]
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[[Category: Aviezer D]]
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[[Category: Butters, T D.]]
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[[Category: Brumshtein B]]
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[[Category: Futerman, A H.]]
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[[Category: Butters TD]]
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[[Category: Greenblatt, H M.]]
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[[Category: Futerman AH]]
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[[Category: Shaaltiel, Y.]]
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[[Category: Greenblatt HM]]
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[[Category: Silman, I.]]
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[[Category: Shaaltiel Y]]
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[[Category: Sussman, J L.]]
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[[Category: Silman I]]
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[[Category: Acid-beta-glucosidase]]
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[[Category: Sussman JL]]
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[[Category: Disease mutation]]
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[[Category: Gaucher disease]]
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[[Category: Glycoprotein]]
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[[Category: Glycosidase]]
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[[Category: Hydrolase]]
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[[Category: Lipid metabolism]]
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[[Category: Lysosome]]
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[[Category: Membrane]]
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[[Category: N-butyl-deoxynojirimycin]]
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[[Category: N-butyl-deoxynojirimycinalternative initiation]]
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[[Category: Sphingolipid metabolism]]
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Current revision

acid-beta-glucosidase with N-butyl-deoxynojirimycin

PDB ID 2v3d

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