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- PDB-9ena: Lysosomal glucocerebrosidase in complex with a stabilizing nanobody -

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Basic information

Entry
Database: PDB / ID: 9ena
TitleLysosomal glucocerebrosidase in complex with a stabilizing nanobody
Components
  • Chains: B
  • Glucosylceramidase
KeywordsHYDROLASE / Glucosidase / Glucosyltransferase / Lipid metabolism / GCase / nanobody / complex / allosteric / stabilizer
Function / homology
Function and homology information


steryl-beta-glucosidase activity / positive regulation of neuronal action potential / beta-glucoside catabolic process / cerebellar Purkinje cell layer formation / termination of signal transduction / galactosylceramidase / galactosylceramidase activity / glucosylceramidase / scavenger receptor binding / positive regulation of protein lipidation ...steryl-beta-glucosidase activity / positive regulation of neuronal action potential / beta-glucoside catabolic process / cerebellar Purkinje cell layer formation / termination of signal transduction / galactosylceramidase / galactosylceramidase activity / glucosylceramidase / scavenger receptor binding / positive regulation of protein lipidation / lymphocyte migration / glucosylceramide catabolic process / regulation of lysosomal protein catabolic process / glucosylceramidase activity / sphingosine biosynthetic process / autophagosome organization / microglial cell proliferation / glucosyltransferase activity / regulation of TOR signaling / response to thyroid hormone / Glycosphingolipid catabolism / microglia differentiation / ceramide biosynthetic process / positive regulation of type 2 mitophagy / lipid storage / lipid glycosylation / brain morphogenesis / positive regulation of protein-containing complex disassembly / response to pH / Hydrolases; Glycosylases; Glycosidases, i.e. enzymes that hydrolyse O- and S-glycosyl compounds / pyramidal neuron differentiation / negative regulation of protein metabolic process / motor behavior / lysosome organization / Transferases; Glycosyltransferases; Hexosyltransferases / neuromuscular process / hematopoietic stem cell proliferation / antigen processing and presentation / response to testosterone / Association of TriC/CCT with target proteins during biosynthesis / response to dexamethasone / negative regulation of interleukin-6 production / homeostasis of number of cells / regulation of macroautophagy / establishment of skin barrier / negative regulation of MAPK cascade / negative regulation of protein-containing complex assembly / cell maturation / mitophagy / cholesterol metabolic process / lysosomal lumen / cellular response to starvation / respiratory electron transport chain / 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 / cellular response to tumor necrosis factor / T cell differentiation in thymus / neuron apoptotic process / negative regulation of neuron apoptotic process / proteasome-mediated ubiquitin-dependent protein catabolic process / lysosome / signaling receptor binding / lysosomal membrane / endoplasmic reticulum / Golgi apparatus / 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)
Lama glama (llama)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.7 Å
AuthorsDal Maso, T. / Versees, W.
Funding support United States, Belgium, 5items
OrganizationGrant numberCountry
Michael J. Fox FoundationMJFF-17240 United States
Michael J. Fox FoundationMJFF-020706 United States
Research Foundation - Flanders (FWO)G031324N Belgium
Other privateSRP50 Belgium
Other privateSRP95 Belgium
CitationJournal: Nat Commun / Year: 2025
Title: Developing nanobodies as allosteric molecular chaperones of glucocerebrosidase function.
Authors: Dal Maso, T. / Sinisgalli, C. / Zilio, G. / Franzin, E. / Tessari, I. / Pardon, E. / Steyaert, J. / Ballet, S. / Greggio, E. / Versees, W. / Plotegher, N.
History
DepositionMar 12, 2024Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jun 4, 2025Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Glucosylceramidase
B: Chains: B
hetero molecules


Theoretical massNumber of molelcules
Total (without water)72,95014
Polymers71,4872
Non-polymers1,46312
Water14,556808
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4260 Å2
ΔGint-119 kcal/mol
Surface area23980 Å2
Unit cell
Length a, b, c (Å)113.209, 113.209, 257.373
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number97
Space group name H-MI422
Space group name HallI42
Symmetry operation#1: x,y,z
#2: -y,x,z
#3: y,-x,z
#4: x,-y,-z
#5: -x,y,-z
#6: -x,-y,z
#7: y,x,-z
#8: -y,-x,-z
#9: x+1/2,y+1/2,z+1/2
#10: -y+1/2,x+1/2,z+1/2
#11: y+1/2,-x+1/2,z+1/2
#12: x+1/2,-y+1/2,-z+1/2
#13: -x+1/2,y+1/2,-z+1/2
#14: -x+1/2,-y+1/2,z+1/2
#15: y+1/2,x+1/2,-z+1/2
#16: -y+1/2,-x+1/2,-z+1/2
Components on special symmetry positions
IDModelComponents
11A-751-

HOH

21A-827-

HOH

31A-1167-

HOH

41A-1184-

HOH

51A-1250-

HOH

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Components

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Protein / Antibody , 2 types, 2 molecules AB

#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.: 1 / Mutation: R495H
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, EC: 3.2.1.104
#2: Antibody Chains: B


Mass: 15847.319 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Lama glama (llama) / Production host: Escherichia coli (E. coli) / Strain (production host): WK6

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Sugars , 2 types, 2 molecules

#3: 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
#4: 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


Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 1 / 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

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Non-polymers , 3 types, 818 molecules

#5: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Mg
#6: Chemical
ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: SO4
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 808 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestN
Has protein modificationY

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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: 2.88 Å3/Da / Density % sol: 57.35 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop
Details: 1.6 M Magnesium sulfate heptahydrate, 0.1 M MES pH6.5

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SOLEIL / Beamline: PROXIMA 2 / Wavelength: 0.9801 Å
DetectorType: DECTRIS EIGER X 9M / Detector: PIXEL / Date: Sep 18, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9801 Å / Relative weight: 1
ReflectionResolution: 1.7→46.86 Å / Num. obs: 78278 / % possible obs: 84.9 % / Redundancy: 17.1 % / Biso Wilson estimate: 15.88 Å2 / CC1/2: 0.998 / Net I/σ(I): 13.4
Reflection shellResolution: 1.7→1.78 Å / Num. unique obs: 3915 / CC1/2: 0.52

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Processing

Software
NameVersionClassification
PHENIX1.20.1_4487refinement
autoPROC1.0.5data processing
XDSdata reduction
Aimless0.7.4data scaling
PHENIX2.8.3phasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.7→46.86 Å / SU ML: 0.1505 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 19.9354
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.1944 3902 4.99 %
Rwork0.1629 74370 -
obs0.1645 78272 85.31 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 20.88 Å2
Refinement stepCycle: LAST / Resolution: 1.7→46.86 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4942 0 84 808 5834
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00795185
X-RAY DIFFRACTIONf_angle_d0.96217075
X-RAY DIFFRACTIONf_chiral_restr0.0574763
X-RAY DIFFRACTIONf_plane_restr0.0088902
X-RAY DIFFRACTIONf_dihedral_angle_d6.3946715
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.7-1.720.228928509X-RAY DIFFRACTION
1.72-1.740.2176411026X-RAY DIFFRACTION32.75
1.74-1.770.2469790.23641258X-RAY DIFFRACTION41.76
1.77-1.790.2455730.2231472X-RAY DIFFRACTION48.27
1.79-1.820.2545880.22361670X-RAY DIFFRACTION54.43
1.82-1.840.27321010.22771887X-RAY DIFFRACTION61.15
1.84-1.870.2291050.21652166X-RAY DIFFRACTION70.05
1.87-1.90.23841210.21332463X-RAY DIFFRACTION79.73
1.9-1.930.28181330.20972692X-RAY DIFFRACTION87.27
1.93-1.970.24381610.19162897X-RAY DIFFRACTION94.06
1.97-2.010.23491530.19153020X-RAY DIFFRACTION98.08
2.01-2.050.22841590.18143089X-RAY DIFFRACTION99.94
2.05-2.090.22131720.16953092X-RAY DIFFRACTION100
2.09-2.140.21211450.16863103X-RAY DIFFRACTION100
2.14-2.20.20571610.1613096X-RAY DIFFRACTION100
2.2-2.250.21811660.15943090X-RAY DIFFRACTION100
2.25-2.320.19861620.15683102X-RAY DIFFRACTION100
2.32-2.40.20571690.15993090X-RAY DIFFRACTION100
2.4-2.480.19711600.16373107X-RAY DIFFRACTION99.97
2.48-2.580.19471710.16723117X-RAY DIFFRACTION100
2.58-2.70.20581710.16893107X-RAY DIFFRACTION100
2.7-2.840.19371730.16613117X-RAY DIFFRACTION100
2.84-3.020.17891620.16613134X-RAY DIFFRACTION100
3.02-3.250.1881770.15613132X-RAY DIFFRACTION100
3.25-3.580.18321600.14073151X-RAY DIFFRACTION100
3.58-4.10.1431710.1293188X-RAY DIFFRACTION100
4.1-5.160.14381580.12973222X-RAY DIFFRACTION100
5.16-46.860.19581820.17223373X-RAY DIFFRACTION99.8

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