2nsx

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{{STRUCTURE_2nsx| PDB=2nsx | SCENE= }}
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==Structure of acid-beta-glucosidase with pharmacological chaperone provides insight into Gaucher disease==
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===Structure of acid-beta-glucosidase with pharmacological chaperone provides insight into Gaucher disease===
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<StructureSection load='2nsx' size='340' side='right' caption='[[2nsx]], [[Resolution|resolution]] 2.11&Aring;' scene=''>
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{{ABSTRACT_PUBMED_17187079}}
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== Structural highlights ==
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<table><tr><td colspan='2'>[[2nsx]] is a 4 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=2NSX OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2NSX FirstGlance]. <br>
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</td></tr><tr><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=IFM:5-HYDROXYMETHYL-3,4-DIHYDROXYPIPERIDINE'>IFM</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=NDG:2-(ACETYLAMINO)-2-DEOXY-A-D-GLUCOPYRANOSE'>NDG</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene><br>
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<tr><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">GBA ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])</td></tr>
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<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>
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<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=2nsx FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2nsx OCA], [http://www.rcsb.org/pdb/explore.do?structureId=2nsx RCSB], [http://www.ebi.ac.uk/pdbsum/2nsx PDBsum]</span></td></tr>
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<table>
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== Disease ==
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[[http://www.uniprot.org/uniprot/GLCM_HUMAN GLCM_HUMAN]] Defects in GBA are the cause of Gaucher disease (GD) [MIM:[http://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:[http://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:[http://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:[http://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:[http://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:[http://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:[http://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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==Disease==
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== Evolutionary Conservation ==
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[[http://www.uniprot.org/uniprot/GLCM_HUMAN GLCM_HUMAN]] Defects in GBA are the cause of Gaucher disease (GD) [MIM:[http://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:[http://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:[http://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:[http://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:[http://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:[http://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:[http://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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[[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/ns/2nsx_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/chain_selection.php?pdb_ID=2ata 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 results from mutations in the lysosomal enzyme acid beta-glucosidase (GCase). Although enzyme replacement therapy has improved the health of some affected individuals, such as those with the prevalent N370S mutation, oral treatment with pharmacological chaperones may be therapeutic in a wider range of tissue compartments by restoring sufficient activity of endogenous mutant GCase. Here we demonstrate that isofagomine (IFG, 1) binds to the GCase active site, and both increases GCase activity in cell lysates and restores lysosomal trafficking in cells containing N370S mutant GCase. We also compare the crystal structures of IFG-bound GCase at low pH with those of glycerol-bound GCase at low pH and apo-GCase at neutral pH. Our data indicate that IFG induces active GCase, which is secured by interactions with Asn370. The design of small molecules that stabilize substrate-bound conformations of mutant proteins may be a general therapeutic strategy for diseases caused by protein misfolding and mistrafficking.
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==About this Structure==
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Structure of acid beta-glucosidase with pharmacological chaperone provides insight into Gaucher disease.,Lieberman RL, Wustman BA, Huertas P, Powe AC Jr, Pine CW, Khanna R, Schlossmacher MG, Ringe D, Petsko GA Nat Chem Biol. 2007 Feb;3(2):101-7. Epub 2006 Dec 24. PMID:17187079<ref>PMID:17187079</ref>
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[[2nsx]] is a 4 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=2NSX OCA].
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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>
==See Also==
==See Also==
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*[[IFG/DG-Cerezyme|IFG/DG-Cerezyme]]
*[[IFG/DG-Cerezyme|IFG/DG-Cerezyme]]
*[[Treatment of Gaucher disease|Treatment of Gaucher disease]]
*[[Treatment of Gaucher disease|Treatment of Gaucher disease]]
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== References ==
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==Reference==
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<references/>
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<ref group="xtra">PMID:017187079</ref><references group="xtra"/><references/>
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__TOC__
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</StructureSection>
[[Category: Glucosylceramidase]]
[[Category: Glucosylceramidase]]
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]

Revision as of 20:18, 30 September 2014

Structure of acid-beta-glucosidase with pharmacological chaperone provides insight into Gaucher disease

2nsx, resolution 2.11Å

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