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- PDB-6q1n: Glucocerebrosidase in complex with pharmacological chaperone IMX8 -

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Basic information

Entry
Database: PDB / ID: 6q1n
TitleGlucocerebrosidase in complex with pharmacological chaperone IMX8
ComponentsGlucosylceramidase
KeywordsHYDROLASE/INHIBITOR / pharmacological chaperone / Gaucher disease / glycosidase / inhibitor / pKa / HYDROLASE / HYDROLASE-INHIBITOR complex
Function / homology
Function and homology information


positive regulation of protein lipidation / steryl-beta-glucosidase activity / beta-glucoside catabolic process / cerebellar Purkinje cell layer formation / positive regulation of neuronal action potential / : / termination of signal transduction / galactosylceramidase / galactosylceramidase activity / lymphocyte migration ...positive regulation of protein lipidation / steryl-beta-glucosidase activity / beta-glucoside catabolic process / cerebellar Purkinje cell layer formation / positive regulation of neuronal action potential / : / termination of signal transduction / galactosylceramidase / galactosylceramidase activity / lymphocyte migration / glucosylceramidase / scavenger receptor binding / glucosylceramide catabolic process / regulation of lysosomal protein catabolic process / autophagosome organization / glucosylceramidase activity / sphingosine biosynthetic process / microglial cell proliferation / regulation of TOR signaling / glucosyltransferase activity / lipid storage / response to thyroid hormone / ceramide biosynthetic process / 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 dexamethasone / response to testosterone / Association of TriC/CCT with target proteins during biosynthesis / glycosyltransferase activity / antigen processing and presentation / negative regulation of interleukin-6 production / homeostasis of number of cells / establishment of skin barrier / regulation of macroautophagy / negative regulation of protein-containing complex assembly / negative regulation of MAP kinase activity / cell maturation / : / cholesterol metabolic process / cellular response to starvation / lysosomal lumen / respiratory electron transport chain / determination of adult lifespan / trans-Golgi network / negative regulation of inflammatory response / autophagy / 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 / proteasome-mediated ubiquitin-dependent protein catabolic 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
Chem-P9V / Glucosylceramidase / Lysosomal acid glucosylceramidase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.526 Å
AuthorsVickers, C. / Withers, S.G. / Boraston, A.B.
Funding support Canada, 1items
OrganizationGrant numberCountry
Canadian Institutes of Health Research (CIHR) Canada
CitationJournal: To Be Published
Title: Pharmacological chaperones for GCase that switch conformation with pH enhance enzyme levels in Gaucher animal models.
Authors: Santana, A.G. / Robinson, K. / Vickers, C. / Chen, H. / Zhou, S. / Boraston, A.B. / Clarke, L.A. / Withers, S.G.
History
DepositionAug 5, 2019Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 19, 2020Provider: 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: Glucosylceramidase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)116,14242
Polymers111,2802
Non-polymers4,86140
Water6,395355
1
A: Glucosylceramidase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)57,87020
Polymers55,6401
Non-polymers2,23019
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Glucosylceramidase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)58,27222
Polymers55,6401
Non-polymers2,63121
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)109.935, 285.060, 91.815
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number20
Space group name H-MC2221
Components on special symmetry positions
IDModelComponents
11B-791-

HOH

21B-857-

HOH

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Components

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Protein , 1 types, 2 molecules AB

#1: Protein Glucosylceramidase / Glucocerebrosidase


Mass: 55640.168 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Cricetulus griseus (Chinese hamster)
References: UniProt: B2R6A7, UniProt: P04062*PLUS, glucosylceramidase

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Sugars , 4 types, 5 molecules

#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: obtained synthetically
DescriptorTypeProgram
DGlcpNAcb1-4DGlcpNAcb1-Glycam 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
[]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{}}}LINUCSPDB-CARE
#3: Polysaccharide alpha-L-fucopyranose-(1-6)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 367.349 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
LFucpa1-6DGlcpNAcb1-Glycam Condensed SequenceGMML 1.0
WURCS=2.0/2,2,1/[a2122h-1b_1-5_2*NCC/3=O][a1221m-1a_1-5]/1-2/a6-b1WURCSPDB2Glycan 1.1.0
[]{[(4+1)][b-D-GlcpNAc]{[(6+1)][a-L-Fucp]{}}}LINUCSPDB-CARE
#4: Polysaccharide alpha-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta- ...alpha-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 586.542 Da / Num. of mol.: 1 / Source method: obtained synthetically
DescriptorTypeProgram
DManpa1-4DGlcpNAcb1-4DGlcpNAcb1-Glycam Condensed SequenceGMML 1.0
WURCS=2.0/2,3,2/[a2122h-1b_1-5_2*NCC/3=O][a1122h-1a_1-5]/1-1-2/a4-b1_b4-c1WURCSPDB2Glycan 1.1.0
[]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{[(4+1)][a-D-Manp]{}}}}LINUCSPDB-CARE
#8: 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.: 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

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Non-polymers , 4 types, 390 molecules

#5: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 16 / Source method: obtained synthetically / Formula: C2H6O2
#6: Chemical
ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 17
Source method: isolated from a genetically manipulated source
Formula: SO4
#7: Chemical ChemComp-P9V / (2R,3S,4S,5R)-2-[2-(methylsulfanyl)ethyl]piperidine-3,4,5-triol


Mass: 207.290 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Formula: C8H17NO3S / Feature type: SUBJECT OF INVESTIGATION
#9: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 355 / Source method: isolated from a natural source / Formula: H2O

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Details

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: 3.27 Å3/Da / Density % sol: 62.36 %
Crystal growTemperature: 291.15 K / Method: vapor diffusion, hanging drop
Details: 1.5 M (NH4)2SO4, 0.1 M Bis Tris (pH 4.9) containing 0.1 M CsCl

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU MICROMAX-007 HF / Wavelength: 1.54178 Å
DetectorType: DECTRIS PILATUS3 R 200K-A / Detector: PIXEL / Date: Dec 8, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54178 Å / Relative weight: 1
ReflectionResolution: 2.52→30 Å / Num. obs: 48354 / % possible obs: 99.7 % / Redundancy: 4.5 % / Biso Wilson estimate: 40.35 Å2 / Rmerge(I) obs: 0.078 / Rpim(I) all: 0.038 / Rrim(I) all: 0.088 / Χ2: 0.909 / Net I/σ(I): 9.5 / Num. measured all: 218036
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsCC1/2Rpim(I) allRrim(I) allΧ2% possible all
2.52-2.562.50.37623770.8850.2870.4760.76198.8
2.56-2.612.60.31923770.9020.2380.40.74899
2.61-2.662.80.32223380.9080.2330.3990.74598.6
2.66-2.712.90.25523970.9410.1790.3130.72899.1
2.71-2.773.10.22823910.9570.1540.2760.70699.2
2.77-2.843.20.22623760.9570.1450.270.74599.7
2.84-2.913.50.19423780.9680.1190.2290.77599.6
2.91-2.993.70.16924010.9740.10.1980.77299.9
2.99-3.083.90.13923930.9840.0790.1610.806100
3.08-3.174.20.12724380.9850.070.1450.84100
3.17-3.294.50.10423810.9890.0550.1190.864100
3.29-3.424.90.09124320.9930.0450.1020.888100
3.42-3.575.50.08324000.9940.0390.0920.889100
3.57-3.766.30.07724200.9960.0330.0840.972100
3.76-46.20.06724310.9970.0290.0730.867100
4-4.316.20.06424330.9960.0280.070.947100
4.31-4.746.20.0624480.9960.0260.0651.034100
4.74-5.426.10.0624650.9970.0260.0660.963100
5.42-6.8160.06324880.9960.0280.0690.972100
6.81-305.40.06225900.9930.0290.0691.305100

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Processing

Software
NameVersionClassification
PHENIX1.13_2998refinement
HKL-2000data scaling
PDB_EXTRACT3.25data extraction
HKL-2000data reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.526→29.923 Å / SU ML: 0.3 / Cross valid method: THROUGHOUT / σ(F): 1.34 / Phase error: 26.14
RfactorNum. reflection% reflection
Rfree0.2383 2215 4.99 %
Rwork0.195 --
obs0.1971 44365 90.83 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso max: 117.82 Å2 / Biso mean: 39.5061 Å2 / Biso min: 18.9 Å2
Refinement stepCycle: final / Resolution: 2.526→29.923 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7710 0 294 355 8359
Biso mean--61.54 40.29 -
Num. residues----983
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection Rwork% reflection obs (%)
2.526-2.58040.3099970.2504170860
2.5804-2.64040.3091000.244189566
2.6404-2.70640.30891110.2448209773
2.7064-2.77950.28931200.239237582
2.7795-2.86120.32861450.242260191
2.8612-2.95350.3391580.2423279698
2.9535-3.0590.28631520.2392287999
3.059-3.18130.27011440.233285199
3.1813-3.32590.26491490.20482855100
3.3259-3.5010.25511770.1996279698
3.501-3.720.21241450.1796284398
3.72-4.00660.22261350.1707279896
4.0066-4.40860.19821500.1613278996
4.4086-5.0440.18061680.1506281797
5.044-6.34490.23351200.1883296399
6.3449-29.9230.20831440.19573087100

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