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- PDB-6ytr: Structure of recombinant human beta-glucocerebrosidase in complex... -

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Basic information

Entry
Database: PDB / ID: 6ytr
TitleStructure of recombinant human beta-glucocerebrosidase in complex with cyclophellitol aziridine inhibitor
ComponentsLysosomal acid glucosylceramidase
KeywordsHYDROLASE / beta-glucocerebrosidase / lysosomal glycoside hydrolase / GH30 / Cyclophellitol aziridine / Inhibitor / Complex
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 / lymphocyte migration ...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 / lymphocyte migration / glucosylceramide catabolic process / regulation of lysosomal protein catabolic process / response to thyroid hormone / glucosylceramidase activity / sphingosine biosynthetic process / autophagosome organization / lysosomal protein catabolic process / microglial cell proliferation / glucosyltransferase activity / regulation of TOR signaling / Glycosphingolipid catabolism / microglia differentiation / lipid storage / ceramide biosynthetic process / positive regulation of type 2 mitophagy / : / brain morphogenesis / Hydrolases; Glycosylases; Glycosidases, i.e. enzymes that hydrolyse O- and S-glycosyl compounds / response to pH / pyramidal neuron differentiation / negative regulation of protein metabolic process / Transferases; Glycosyltransferases; Hexosyltransferases / lysosome organization / neuromuscular process / response to dexamethasone / hematopoietic stem cell proliferation / antigen processing and presentation / response to testosterone / Association of TriC/CCT with target proteins during biosynthesis / motor behavior / negative regulation of interleukin-6 production / homeostasis of number of cells / regulation of macroautophagy / establishment of skin barrier / negative regulation of protein-containing complex assembly / cholesterol metabolic process / mitophagy / cell maturation / negative regulation of MAPK cascade / lysosomal lumen / cellular response to starvation / determination of adult lifespan / respiratory electron transport chain / trans-Golgi network / autophagy / negative regulation of inflammatory response / response to estrogen / cellular response to tumor necrosis factor / positive regulation of proteasomal ubiquitin-dependent protein catabolic process / T cell differentiation in thymus / neuron apoptotic process / proteasome-mediated ubiquitin-dependent protein catabolic process / negative regulation of neuron apoptotic 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
Chem-PO8 / Lysosomal acid glucosylceramidase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.7 Å
AuthorsRowland, R.J. / Davies, G.J.
Funding support United Kingdom, 1items
OrganizationGrant numberCountry
Biotechnology and Biological Sciences Research Council (BBSRC)BB/M011151/1 United Kingdom
CitationJournal: Chemistry / Year: 2021
Title: Design, Synthesis and Structural Analysis of Glucocerebrosidase Imaging Agents.
Authors: Rowland, R.J. / Chen, Y. / Breen, I. / Wu, L. / Offen, W.A. / Beenakker, T.J. / Su, Q. / van den Nieuwendijk, A.M.C.H. / Aerts, J.M.F.G. / Artola, M. / Overkleeft, H.S. / Davies, G.J.
History
DepositionApr 24, 2020Deposition site: PDBE / Processing site: PDBE
Revision 1.0May 12, 2021Provider: repository / Type: Initial release
Revision 1.1Nov 24, 2021Group: Data collection / Database references / Structure summary
Category: citation / citation_author ...citation / citation_author / database_2 / diffrn_source / pdbx_database_proc / pdbx_entity_branch_descriptor / struct
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _diffrn_source.pdbx_synchrotron_site / _struct.pdbx_center_of_mass_x / _struct.pdbx_center_of_mass_y / _struct.pdbx_center_of_mass_z
Revision 1.2Dec 8, 2021Group: Data collection / Database references / Category: citation / citation_author / diffrn_source
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID / _diffrn_source.pdbx_synchrotron_site
Revision 1.3Jan 24, 2024Group: Data collection / Derived calculations / Refinement description
Category: atom_type / chem_comp_atom ...atom_type / chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model
Item: _atom_type.pdbx_N_electrons / _atom_type.pdbx_scat_Z
Revision 1.4Oct 16, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature / Item: _pdbx_entry_details.has_protein_modification

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
AAA: Lysosomal acid glucosylceramidase
BBB: Lysosomal acid glucosylceramidase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)117,01359
Polymers111,3182
Non-polymers5,69557
Water15,799877
1
AAA: Lysosomal acid glucosylceramidase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)58,41028
Polymers55,6591
Non-polymers2,75127
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
BBB: Lysosomal acid glucosylceramidase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)58,60331
Polymers55,6591
Non-polymers2,94430
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)53.155, 156.779, 68.230
Angle α, β, γ (deg.)90.000, 102.116, 90.000
Int Tables number4
Space group name H-MP1211

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Components

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Protein , 1 types, 2 molecules AAABBB

#1: Protein Lysosomal acid glucosylceramidase / Lysosomal acid GCase / Acid beta-glucosidase / Alglucerase / Beta-glucocerebrosidase / Beta-GC / ...Lysosomal acid GCase / Acid beta-glucosidase / Alglucerase / Beta-glucocerebrosidase / Beta-GC / Cholesterol glucosyltransferase / SGTase / Cholesteryl-beta-glucosidase / D-glucosyl-N-acylsphingosine glucohydrolase / Imiglucerase


Mass: 55659.219 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Details: Recombinant human beta-glucocerebrosidase missing its 40-amino acid signalling sequence
Source: (gene. exp.) Homo sapiens (human) / Gene: GBA, GC, GLUC / Production host: Trichoplusia ni (cabbage looper)
References: UniProt: P04062, glucosylceramidase, Transferases; Glycosyltransferases; Hexosyltransferases, EC: 3.2.1.104

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Sugars , 4 types, 4 molecules

#2: Polysaccharide alpha-D-mannopyranose-(1-6)-beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1- ...alpha-D-mannopyranose-(1-6)-beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 748.682 Da / Num. of mol.: 1 / Source method: isolated from a natural source
DescriptorTypeProgram
DManpa1-6DManpb1-4DGlcpNAcb1-4DGlcpNAcb1-Glycam Condensed SequenceGMML 1.0
WURCS=2.0/3,4,3/[a2122h-1b_1-5_2*NCC/3=O][a1122h-1b_1-5][a1122h-1a_1-5]/1-1-2-3/a4-b1_b4-c1_c6-d1WURCSPDB2Glycan 1.1.0
[]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-Manp]{[(6+1)][a-D-Manp]{}}}}}LINUCSPDB-CARE
#3: Polysaccharide beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta- ...beta-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: isolated from a natural source
DescriptorTypeProgram
DManpb1-4DGlcpNAcb1-4DGlcpNAcb1-Glycam Condensed SequenceGMML 1.0
WURCS=2.0/2,3,2/[a2122h-1b_1-5_2*NCC/3=O][a1122h-1b_1-5]/1-1-2/a4-b1_b4-c1WURCSPDB2Glycan 1.1.0
[]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-Manp]{}}}}LINUCSPDB-CARE
#4: 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 natural source
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
#7: 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: isolated from a natural source / 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 , 5 types, 930 molecules

#5: Chemical ChemComp-PO8 / (1~{R},2~{S},3~{S},4~{S},5~{R},6~{R})-5-azanyl-6-(hydroxymethyl)cyclohexane-1,2,3,4-tetrol


Mass: 194.206 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Formula: C7H16NO5 / Feature type: SUBJECT OF INVESTIGATION
#6: Chemical
ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 7 / Source method: isolated from a natural source / Formula: SO4
#8: Chemical...
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 42 / Source method: obtained synthetically / Formula: C2H6O2
#9: Chemical ChemComp-NA / SODIUM ION


Mass: 22.990 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Na
#10: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 877 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestY
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: 3.07 Å3/Da / Density % sol: 59.88 %
Crystal growTemperature: 291 K / Method: vapor diffusion, sitting drop
Details: 0.2 M Na2SO4, 14% (v/v) PEG3350, 0.25 M HEPES pH 7.0

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I02 / Wavelength: 0.9762 Å
DetectorType: DECTRIS EIGER2 X 16M / Detector: PIXEL / Date: Mar 4, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9762 Å / Relative weight: 1
ReflectionResolution: 1.7→66.799 Å / Num. obs: 119361 / % possible obs: 99.9 % / Redundancy: 6.6 % / CC1/2: 0.994 / Rmerge(I) obs: 0.159 / Rpim(I) all: 0.064 / Net I/σ(I): 6.3
Reflection shellResolution: 1.7→1.73 Å / Rmerge(I) obs: 1.83 / Mean I/σ(I) obs: 1 / Num. unique obs: 5867 / CC1/2: 0.547 / Rpim(I) all: 1.07 / % possible all: 99.7

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Processing

Software
NameVersionClassification
REFMAC5.8.0258refinement
xia2data reduction
Aimlessdata scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2NT0

2nt0


Resolution: 1.7→66.799 Å / Cor.coef. Fo:Fc: 0.973 / Cor.coef. Fo:Fc free: 0.955 / WRfactor Rfree: 0.209 / WRfactor Rwork: 0.163 / SU B: 2.808 / SU ML: 0.086 / Average fsc free: 0.8881 / Average fsc work: 0.9009 / Cross valid method: FREE R-VALUE / ESU R: 0.095 / ESU R Free: 0.1
Details: Hydrogens have been added in their riding positions
RfactorNum. reflection% reflection
Rfree0.2026 5927 4.966 %
Rwork0.1592 113434 -
all0.161 --
obs-119361 99.883 %
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK BULK SOLVENT
Displacement parametersBiso mean: 24.919 Å2
Baniso -1Baniso -2Baniso -3
1-0.659 Å20 Å20.144 Å2
2--0.625 Å20 Å2
3----1.233 Å2
Refinement stepCycle: LAST / Resolution: 1.7→66.799 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7833 0 360 877 9070
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.010.0138509
X-RAY DIFFRACTIONr_bond_other_d0.0010.0177713
X-RAY DIFFRACTIONr_angle_refined_deg1.5911.67711544
X-RAY DIFFRACTIONr_angle_other_deg1.3721.59117891
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.49751054
X-RAY DIFFRACTIONr_dihedral_angle_other_1_deg48.622012
X-RAY DIFFRACTIONr_dihedral_angle_2_deg33.94821.898411
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.43815.0891288
X-RAY DIFFRACTIONr_dihedral_angle_4_deg19.21546
X-RAY DIFFRACTIONr_chiral_restr0.0820.21095
X-RAY DIFFRACTIONr_gen_planes_refined0.0090.029309
X-RAY DIFFRACTIONr_gen_planes_other0.0010.021812
X-RAY DIFFRACTIONr_nbd_refined0.2090.21694
X-RAY DIFFRACTIONr_symmetry_nbd_other0.1820.27427
X-RAY DIFFRACTIONr_nbtor_refined0.1690.24011
X-RAY DIFFRACTIONr_symmetry_nbtor_other0.0920.23567
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1640.2698
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_other0.1080.22
X-RAY DIFFRACTIONr_metal_ion_refined0.1630.27
X-RAY DIFFRACTIONr_symmetry_nbd_refined0.2450.228
X-RAY DIFFRACTIONr_nbd_other0.310.284
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_refined0.2240.228
X-RAY DIFFRACTIONr_mcbond_it1.7042.44029
X-RAY DIFFRACTIONr_mcbond_other1.7042.44028
X-RAY DIFFRACTIONr_mcangle_it2.3013.5945052
X-RAY DIFFRACTIONr_mcangle_other2.33.5955053
X-RAY DIFFRACTIONr_scbond_it2.572.7724480
X-RAY DIFFRACTIONr_scbond_other2.572.7734481
X-RAY DIFFRACTIONr_scangle_it3.6284.0186492
X-RAY DIFFRACTIONr_scangle_other3.6284.0186493
X-RAY DIFFRACTIONr_lrange_it5.16329.7239658
X-RAY DIFFRACTIONr_lrange_other5.16229.7229658
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.7-1.7440.3024450.2988349X-RAY DIFFRACTION99.5585
1.744-1.7920.2954470.2648122X-RAY DIFFRACTION99.7555
1.792-1.8440.2734300.2417939X-RAY DIFFRACTION99.7973
1.844-1.9010.2623980.2227714X-RAY DIFFRACTION99.8892
1.901-1.9630.273780.2347455X-RAY DIFFRACTION99.9107
1.963-2.0320.2333900.1787242X-RAY DIFFRACTION99.9738
2.032-2.1080.2163730.1916956X-RAY DIFFRACTION99.9727
2.108-2.1950.1993920.1496694X-RAY DIFFRACTION100
2.195-2.2920.2033360.1596416X-RAY DIFFRACTION99.9408
2.292-2.4040.1982940.1316215X-RAY DIFFRACTION99.9539
2.404-2.5340.1943280.1345859X-RAY DIFFRACTION100
2.534-2.6880.2022750.1415533X-RAY DIFFRACTION99.9656
2.688-2.8730.192690.1355224X-RAY DIFFRACTION100
2.873-3.1030.1762390.1434900X-RAY DIFFRACTION100
3.103-3.3990.1922190.1554483X-RAY DIFFRACTION100
3.399-3.80.1912000.1464077X-RAY DIFFRACTION99.9766
3.8-4.3880.1741720.1263564X-RAY DIFFRACTION99.9732
4.388-5.3730.1461530.1233030X-RAY DIFFRACTION100
5.373-7.5940.2131170.162369X-RAY DIFFRACTION100
7.594-9.310.194720.171293X-RAY DIFFRACTION99.8537

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