View source for 5lvx


==Crystal structure of glucocerebrosidase with an inhibitory quinazoline modulator==
<StructureSection load='5lvx' size='340' side='right'caption='[[5lvx]], [[Resolution|resolution]] 2.20&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[5lvx]] 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=5LVX OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5LVX FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=79B:11-[(2~{R})-2-[(2-pyridin-3-ylquinazolin-4-yl)amino]-2,3-dihydro-1~{H}-inden-5-yl]undec-10-ynoic+acid'>79B</scene>, <scene name='pdbligand=7E4:11-[(2~{S})-2-[(2-pyridin-3-ylquinazolin-4-yl)amino]-2,3-dihydro-1~{H}-inden-5-yl]undec-10-ynoic+acid'>7E4</scene>, <scene name='pdbligand=BMA:BETA-D-MANNOSE'>BMA</scene>, <scene name='pdbligand=MAN:ALPHA-D-MANNOSE'>MAN</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</scene></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=5lvx FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5lvx OCA], [https://pdbe.org/5lvx PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5lvx RCSB], [https://www.ebi.ac.uk/pdbsum/5lvx PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5lvx ProSAT]</span></td></tr>
</table>
== Disease ==
[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> 
== Function ==
[https://www.uniprot.org/uniprot/GLCM_HUMAN GLCM_HUMAN] 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
beta-Glucocerebrosidase (GCase) mutations cause Gaucher's disease and are a high risk factor in Parkinson's disease. The implementation of a small molecule modulator is a strategy to restore proper folding and lysosome delivery of degradation-prone mutant GCase. Here, we present a potent quinazoline modulator, JZ-4109, which stabilizes wild-type and N370S mutant GCase and increases GCase abundance in patient-derived fibroblast cells. We then developed a covalent modification strategy using a lysine targeted inactivator (JZ-5029) for in vitro mechanistic studies. By using native top-down mass spectrometry, we located two potentially covalently modified lysines. We obtained the first crystal structure, at 2.2 A resolution, of a GCase with a noniminosugar modulator covalently bound, and were able to identify the exact lysine residue modified (Lys346) and reveal an allosteric binding site. GCase dimerization was induced by our modulator binding, which was observed by native mass spectrometry, its crystal structure, and size exclusion chromatography with a multiangle light scattering detector. Finally, the dimer form was confirmed by negative staining transmission electron microscopy studies. Our newly discovered allosteric site and observed GCase dimerization provide a new mechanistic insight into GCase and its noniminosugar modulators and facilitate the rational design of novel GCase modulators for Gaucher's disease and Parkinson's disease.

beta-Glucocerebrosidase Modulators Promote Dimerization of beta-Glucocerebrosidase and Reveal an Allosteric Binding Site.,Zheng J, Chen L, Skinner OS, Ysselstein D, Remis J, Lansbury P, Skerlj R, Mrosek M, Heunisch U, Krapp S, Charrow J, Schwake M, Kelleher NL, Silverman RB, Krainc D J Am Chem Soc. 2018 Apr 30. doi: 10.1021/jacs.7b13003. PMID:29676907<ref>PMID:29676907</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 5lvx" style="background-color:#fffaf0;"></div>

==See Also==
*[[Acid-beta-glucosidase 3D structures|Acid-beta-glucosidase 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Charrow J]]
[[Category: Chen L]]
[[Category: Heunisch U]]
[[Category: Kelleher NL]]
[[Category: Krainc D]]
[[Category: Krapp S]]
[[Category: Lansbury P]]
[[Category: Mrosek M]]
[[Category: Schwake M]]
[[Category: Silverman RB]]
[[Category: Skerlj R]]
[[Category: Skinner OS]]
[[Category: Weigand S]]
[[Category: Zheng J]]