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- PDB-8p3e: Crystal structure of glucocerebrosidase in complex with allosteri... -

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Basic information

Entry
Database: PDB / ID: 8p3e
TitleCrystal structure of glucocerebrosidase in complex with allosteric activator
ComponentsGlucosylceramidase
KeywordsHYDROLASE / Activator / lysosome / glycolipid metabolism
Function / homology
Function and homology information


positive regulation of protein lipidation / steryl-beta-glucosidase activity / beta-glucoside catabolic process / positive regulation of neuronal action potential / cerebellar Purkinje cell layer formation / galactosylceramidase / termination of signal transduction / galactosylceramidase activity / positive regulation of autophagy of mitochondrion in response to mitochondrial depolarization / lymphocyte migration ...positive regulation of protein lipidation / steryl-beta-glucosidase activity / beta-glucoside catabolic process / positive regulation of neuronal action potential / cerebellar Purkinje cell layer formation / galactosylceramidase / termination of signal transduction / galactosylceramidase activity / positive regulation of autophagy of mitochondrion in response to mitochondrial depolarization / lymphocyte migration / glucosylceramidase / glucosylceramide catabolic process / scavenger receptor binding / regulation of lysosomal protein catabolic process / sphingosine biosynthetic process / autophagosome organization / glucosylceramidase activity / microglial cell proliferation / regulation of TOR signaling / glucosyltransferase activity / ceramide biosynthetic process / lipid storage / response to thyroid hormone / microglia differentiation / Glycosphingolipid catabolism / pyramidal neuron differentiation / lipid glycosylation / brain morphogenesis / Hydrolases; Glycosylases; Glycosidases, i.e. enzymes that hydrolyse O- and S-glycosyl compounds / response to pH / positive regulation of protein-containing complex disassembly / motor behavior / neuromuscular process / Transferases; Glycosyltransferases; Hexosyltransferases / hematopoietic stem cell proliferation / lysosome organization / response to testosterone / response to dexamethasone / Association of TriC/CCT with target proteins during biosynthesis / negative regulation of interleukin-6 production / homeostasis of number of cells / antigen processing and presentation / regulation of macroautophagy / establishment of skin barrier / negative regulation of protein-containing complex assembly / positive regulation of protein dephosphorylation / cell maturation / respiratory electron transport chain / cellular response to starvation / cholesterol metabolic process / lysosomal lumen / negative regulation of MAP kinase activity / determination of adult lifespan / trans-Golgi network / autophagy / negative regulation of inflammatory response / response to estrogen / positive regulation of proteasomal ubiquitin-dependent protein catabolic process / T cell differentiation in thymus / cellular response to tumor necrosis factor / proteasome-mediated ubiquitin-dependent protein catabolic process / neuron apoptotic process / negative regulation of neuron apoptotic process / lysosome / lysosomal membrane / signaling receptor binding / Golgi apparatus / endoplasmic reticulum / extracellular exosome
Similarity search - Function
Glycosyl hydrolase family 30, TIM-barrel domain / Glycosyl hydrolase family 30 TIM-barrel domain / Glycosyl hydrolase family 30, beta sandwich domain / Glycosyl hydrolase family 30 beta sandwich domain / Glycoside hydrolase family 30 / Glycoside hydrolase superfamily
Similarity search - Domain/homology
: / Lysosomal acid glucosylceramidase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.75 Å
AuthorsSchulze, M.-S.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Chemmedchem / Year: 2024
Title: Identification of ss-Glucocerebrosidase Activators for Glucosylceramide hydrolysis.
Authors: Schulze, M.E.D. / Scholz, D. / Jnoff, E. / Hall, A. / Melin, J. / Sands, Z.A. / Rodriguez, E. / Andre, V.M.
History
DepositionMay 17, 2023Deposition site: PDBE / Processing site: PDBE
Revision 1.0Mar 6, 2024Provider: repository / Type: Initial release
Revision 1.1Apr 24, 2024Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
Revision 1.2May 1, 2024Group: Database references / Category: citation / citation_author
Item: _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Glucosylceramidase
B: Glucosylceramidase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)112,5786
Polymers111,2802
Non-polymers1,2984
Water8,179454
1
A: Glucosylceramidase
B: Glucosylceramidase
hetero molecules

A: Glucosylceramidase
B: Glucosylceramidase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)225,15612
Polymers222,5614
Non-polymers2,5958
Water724
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation3_654-x+1,y,-z-1/21
Buried area8580 Å2
ΔGint-18 kcal/mol
Surface area69010 Å2
MethodPISA
Unit cell
Length a, b, c (Å)110.310, 285.640, 91.870
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number20
Space group name H-MC2221
Components on special symmetry positions
IDModelComponents
11A-670-

HOH

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Components

#1: Protein Glucosylceramidase / / Acid beta-glucosidase / Alglucerase / Beta-glucocerebrosidase / Beta-GC / D-glucosyl-N- ...Acid beta-glucosidase / Alglucerase / Beta-glucocerebrosidase / Beta-GC / D-glucosyl-N-acylsphingosine glucohydrolase / Imiglucerase


Mass: 55640.168 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GBA, GC, GLUC / Production host: Cricetulus griseus (Chinese hamster)
References: UniProt: P04062, glucosylceramidase, Transferases; Glycosyltransferases; Hexosyltransferases, steryl-beta-glucosidase
#2: Polysaccharide 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 424.401 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DGlcpNAcb1-4DGlcpNAcb1-ROHGlycam Condensed SequenceGMML 1.0
WURCS=2.0/1,2,1/[a2122h-1b_1-5_2*NCC/3=O]/1-1/a4-b1WURCSPDB2Glycan 1.1.0
[][D-1-deoxy-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{}}LINUCSPDB-CARE
#3: Sugar ChemComp-NAG / 2-acetamido-2-deoxy-beta-D-glucopyranose / N-acetyl-beta-D-glucosamine / 2-acetamido-2-deoxy-beta-D-glucose / 2-acetamido-2-deoxy-D-glucose / 2-acetamido-2-deoxy-glucose / N-ACETYL-D-GLUCOSAMINE / N-Acetylglucosamine


Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C8H15NO6
IdentifierTypeProgram
DGlcpNAcbCONDENSED IUPAC CARBOHYDRATE SYMBOLGMML 1.0
N-acetyl-b-D-glucopyranosamineCOMMON NAMEGMML 1.0
b-D-GlcpNAcIUPAC CARBOHYDRATE SYMBOLPDB-CARE 1.0
GlcNAcSNFG CARBOHYDRATE SYMBOLGMML 1.0
#4: Chemical ChemComp-WSI / 2-[[3-[(4-chlorophenyl)carbamoyl]phenyl]sulfonylamino]benzoic acid


Mass: 430.862 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C20H15ClN2O5S / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 454 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

CrystalDensity Matthews: 3.25 Å3/Da / Density % sol: 62.17 %
Crystal growTemperature: 291 K / Method: vapor diffusion / Details: 2 M (NH4)2SO4, 0.1 M Bis-Tris pH 5.5

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SOLEIL / Beamline: PROXIMA 1 / Wavelength: 0.97857 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Nov 22, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97857 Å / Relative weight: 1
ReflectionResolution: 1.75→47.61 Å / Num. obs: 278631 / % possible obs: 98.79 % / Redundancy: 4.5 % / Rmerge(I) obs: 0.039 / Net I/σ(I): 18.4
Reflection shellResolution: 1.75→1.8 Å / Rmerge(I) obs: 0.538 / Num. unique obs: 10430

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Processing

Software
NameVersionClassification
PHENIX(1.18.2_3874: ???)refinement
XDSdata reduction
XDSdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.75→47.61 Å / SU ML: 0.22 / Cross valid method: FREE R-VALUE / σ(F): 1.01 / Phase error: 24.74 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2137 13955 5.01 %
Rwork0.1903 --
obs0.1915 278631 98.79 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 1.75→47.61 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7858 0 85 454 8397
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.018187
X-RAY DIFFRACTIONf_angle_d1.04111166
X-RAY DIFFRACTIONf_dihedral_angle_d16.6382921
X-RAY DIFFRACTIONf_chiral_restr0.0631217
X-RAY DIFFRACTIONf_plane_restr0.0081438
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.75-1.770.38424400.40258339X-RAY DIFFRACTION94
1.77-1.790.37674650.34858766X-RAY DIFFRACTION99
1.79-1.810.32334670.3078814X-RAY DIFFRACTION99
1.81-1.840.31054650.28848881X-RAY DIFFRACTION98
1.84-1.860.31484650.28148751X-RAY DIFFRACTION99
1.86-1.890.26344570.24148778X-RAY DIFFRACTION98
1.89-1.910.26094710.22328910X-RAY DIFFRACTION99
1.91-1.940.26064590.21568783X-RAY DIFFRACTION99
1.94-1.970.23164680.20438777X-RAY DIFFRACTION99
1.97-2.010.24134720.20238864X-RAY DIFFRACTION99
2.01-2.040.24684660.19298901X-RAY DIFFRACTION99
2.04-2.080.244650.19938829X-RAY DIFFRACTION99
2.08-2.120.21914600.19558860X-RAY DIFFRACTION99
2.12-2.160.2494650.1988777X-RAY DIFFRACTION99
2.16-2.210.24624650.19258852X-RAY DIFFRACTION99
2.21-2.260.22714630.18668777X-RAY DIFFRACTION98
2.26-2.310.20934760.18298871X-RAY DIFFRACTION100
2.31-2.380.19524610.18018866X-RAY DIFFRACTION99
2.38-2.450.2234700.18398896X-RAY DIFFRACTION100
2.45-2.530.21774650.19298920X-RAY DIFFRACTION99
2.53-2.620.20234660.19038854X-RAY DIFFRACTION99
2.62-2.720.21474720.18798882X-RAY DIFFRACTION99
2.72-2.840.21234600.19628844X-RAY DIFFRACTION99
2.84-2.990.244700.19948842X-RAY DIFFRACTION99
2.99-3.180.20754680.19678886X-RAY DIFFRACTION99
3.18-3.430.21184700.18498879X-RAY DIFFRACTION99
3.43-3.770.18944660.17768765X-RAY DIFFRACTION99
3.77-4.320.19054650.168825X-RAY DIFFRACTION99
4.32-5.440.16564650.1548881X-RAY DIFFRACTION99
5.44-47.610.20284680.19868806X-RAY DIFFRACTION98

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