3gxm

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{{STRUCTURE_3gxm| PDB=3gxm | SCENE= }}
 
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===Crystal structure of acid-beta-glucosidase at pH 4.5, phosphate crystallization condition===
 
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{{ABSTRACT_PUBMED_19374450}}
 
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==Disease==
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==Crystal structure of acid-beta-glucosidase at pH 4.5, phosphate crystallization condition==
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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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<StructureSection load='3gxm' size='340' side='right'caption='[[3gxm]], [[Resolution|resolution]] 2.20&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[3gxm]] is a 4 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=3GXM OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3GXM 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]] 2.2&#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=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</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=3gxm FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3gxm OCA], [https://pdbe.org/3gxm PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3gxm RCSB], [https://www.ebi.ac.uk/pdbsum/3gxm PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3gxm ProSAT]</span></td></tr>
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</table>
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== Disease ==
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[https://www.uniprot.org/uniprot/GBA1_HUMAN GBA1_HUMAN] Gaucher disease type 3;Gaucher disease-ophthalmoplegia-cardiovascular calcification syndrome;Gaucher disease type 1;Hereditary late-onset Parkinson disease;Gaucher disease type 2;Fetal Gaucher disease;NON RARE IN EUROPE: Dementia with Lewy body;NON RARE IN EUROPE: Parkinson disease. The disease is caused by variants affecting the gene represented in this entry. The disease is caused by variants affecting the gene represented in this entry. The disease is caused by variants affecting the gene represented in this entry. The disease is caused by variants affecting the gene represented in this entry. The disease is caused by variants affecting the gene represented in this entry. The disease is caused by variants affecting the gene represented in this entry. 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:10352942</ref> Disease susceptibility may be associated with variants affecting the gene represented in this entry.
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== Function ==
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[https://www.uniprot.org/uniprot/GBA1_HUMAN GBA1_HUMAN] Glucosylceramidase that catalyzes, within the lysosomal compartment, the hydrolysis of glucosylceramides/GlcCers (such as beta-D-glucosyl-(1<->1')-N-acylsphing-4-enine) into free ceramides (such as N-acylsphing-4-enine) and glucose (PubMed:15916907, PubMed:24211208, PubMed:32144204, PubMed:9201993). Plays a central role in the degradation of complex lipids and the turnover of cellular membranes (PubMed:27378698). Through the production of ceramides, participates in the PKC-activated salvage pathway of ceramide formation (PubMed:19279011). Catalyzes the glucosylation of cholesterol, through a transglucosylation reaction where glucose is transferred from GlcCer to cholesterol (PubMed:24211208, PubMed:26724485, PubMed:32144204). GlcCer containing mono-unsaturated fatty acids (such as beta-D-glucosyl-N-(9Z-octadecenoyl)-sphing-4-enine) are preferred as glucose donors for cholesterol glucosylation when compared with GlcCer containing same chain length of saturated fatty acids (such as beta-D-glucosyl-N-octadecanoyl-sphing-4-enine) (PubMed:24211208). Under specific conditions, may alternatively catalyze the reverse reaction, transferring glucose from cholesteryl 3-beta-D-glucoside to ceramide (Probable) (PubMed:26724485). Can also hydrolyze cholesteryl 3-beta-D-glucoside producing glucose and cholesterol (PubMed:24211208, PubMed:26724485). Catalyzes the hydrolysis of galactosylceramides/GalCers (such as beta-D-galactosyl-(1<->1')-N-acylsphing-4-enine), as well as the transfer of galactose between GalCers and cholesterol in vitro, but with lower activity than with GlcCers (PubMed:32144204). Contrary to GlcCer and GalCer, xylosylceramide/XylCer (such as beta-D-xyosyl-(1<->1')-N-acylsphing-4-enine) is not a good substrate for hydrolysis, however it is a good xylose donor for transxylosylation activity to form cholesteryl 3-beta-D-xyloside (PubMed:33361282).<ref>PMID:15916907</ref> <ref>PMID:19279011</ref> <ref>PMID:24211208</ref> <ref>PMID:26724485</ref> <ref>PMID:27378698</ref> <ref>PMID:32144204</ref> <ref>PMID:33361282</ref> <ref>PMID:9201993</ref> <ref>PMID:32144204</ref>
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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/gx/3gxm_consurf.spt"</scriptWhenChecked>
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<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview03.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=3gxm 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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Human lysosomal enzymes acid-beta-glucosidase (GCase) and acid-alpha-galactosidase (alpha-Gal A) hydrolyze the sphingolipids glucosyl- and globotriaosylceramide, respectively, and mutations in these enzymes lead to the lipid metabolism disorders Gaucher and Fabry disease, respectively. We have investigated the structure and stability of GCase and alpha-Gal A in a neutral-pH environment reflective of the endoplasmic reticulum and an acidic-pH environment reflective of the lysosome. These details are important for the development of pharmacological chaperone therapy for Gaucher and Fabry disease, in which small molecules bind mutant enzymes in the ER to enable the mutant enzyme to meet quality control requirements for lysosomal trafficking. We report crystal structures of apo GCase at pH 4.5, at pH 5.5, and in complex with the pharmacological chaperone isofagomine (IFG) at pH 7.5. We also present thermostability analysis of GCase at pH 7.4 and 5.2 using differential scanning calorimetry. We compare our results with analogous experiments using alpha-Gal A and the chaperone 1-deoxygalactonijirimycin (DGJ), including the first structure of alpha-Gal A with DGJ. Both GCase and alpha-Gal A are more stable at lysosomal pH with and without their respective iminosugars bound, and notably, the stability of the GCase-IFG complex is pH sensitive. We show that the conformations of the active site loops in GCase are sensitive to ligand binding but not pH, whereas analogous galactose- or DGJ-dependent conformational changes in alpha-Gal A are not seen. Thermodynamic parameters obtained from alpha-Gal A unfolding indicate two-state, van't Hoff unfolding in the absence of the iminosugar at neutral and lysosomal pH, and non-two-state unfolding in the presence of DGJ. Taken together, these results provide insight into how GCase and alpha-Gal A are thermodynamically stabilized by iminosugars and suggest strategies for the development of new pharmacological chaperones for lysosomal storage disorders.
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==About this Structure==
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Effects of pH and Iminosugar Pharmacological Chaperones on Lysosomal Glycosidase Structure and Stability.,Lieberman RL, D'aquino JA, Ringe D, Petsko GA Biochemistry. 2009 May 1. PMID:19374450<ref>PMID:19374450</ref>
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[[3gxm]] 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=3GXM OCA].
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==See Also==
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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*[[Acid-beta-glucosidase|Acid-beta-glucosidase]]
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</div>
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*[[Beta-glucosidase|Beta-glucosidase]]
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<div class="pdbe-citations 3gxm" style="background-color:#fffaf0;"></div>
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==Reference==
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==See Also==
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<ref group="xtra">PMID:019374450</ref><references group="xtra"/><references/>
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*[[Acid-beta-glucosidase 3D structures|Acid-beta-glucosidase 3D structures]]
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[[Category: Glucosylceramidase]]
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*[[Beta-glucosidase 3D structures|Beta-glucosidase 3D structures]]
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== References ==
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<references/>
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__TOC__
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</StructureSection>
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
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[[Category: Lieberman, R L.]]
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[[Category: Large Structures]]
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[[Category: Alternative initiation]]
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[[Category: Lieberman RL]]
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[[Category: Disease mutation]]
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[[Category: Disulfide bond]]
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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: Ichthyosis]]
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[[Category: Lipid metabolism]]
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[[Category: Lysosome]]
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[[Category: Membrane]]
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[[Category: Sphingolipid metabolism]]
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Current revision

Crystal structure of acid-beta-glucosidase at pH 4.5, phosphate crystallization condition

PDB ID 3gxm

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