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- PDB-6q6n: Crystal structure of recombinant human beta-glucocerebrosidase in... -

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Basic information

Entry
Database: PDB / ID: 6q6n
TitleCrystal structure of recombinant human beta-glucocerebrosidase in complex with biphenyl-cyclophellitol inhibitor (ME655)
ComponentsGlucosylceramidase
KeywordsHYDROLASE / RETAINING BETA-GLUCOSIDASE
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 / 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 / Golgi alpha-mannosidase II / Glycosidases / Glycoside hydrolase superfamily / TIM Barrel / Alpha-Beta Barrel ...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 / Golgi alpha-mannosidase II / Glycosidases / Glycoside hydrolase superfamily / TIM Barrel / Alpha-Beta Barrel / Immunoglobulin-like / Sandwich / Mainly Beta / Alpha Beta
Similarity search - Domain/homology
ACETATE ION / Chem-HK2 / Lysosomal acid glucosylceramidase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.63 Å
AuthorsRowland, R.J. / Davies, G.J.
Funding support United Kingdom, 1items
OrganizationGrant numberCountry
Biotechnology and Biological Sciences Research CouncilBB/M011151/1 United Kingdom
CitationJournal: J.Am.Chem.Soc. / Year: 2019
Title: Functionalized Cyclophellitols Are Selective Glucocerebrosidase Inhibitors and Induce a Bona Fide Neuropathic Gaucher Model in Zebrafish.
Authors: Artola, M. / Kuo, C.L. / Lelieveld, L.T. / Rowland, R.J. / van der Marel, G.A. / Codee, J.D.C. / Boot, R.G. / Davies, G.J. / Aerts, J.M.F.G. / Overkleeft, H.S.
History
DepositionDec 11, 2018Deposition site: PDBE / Processing site: PDBE
Revision 1.0Mar 27, 2019Provider: repository / Type: Initial release
Revision 1.1May 8, 2019Group: Data collection / Derived calculations / Category: diffrn_source / struct_conn / Item: _diffrn_source.pdbx_synchrotron_site
Revision 1.2Jul 10, 2019Group: Data collection / Category: diffrn_source / Item: _diffrn_source.pdbx_synchrotron_site
Revision 2.0Jul 29, 2020Group: Advisory / Atomic model ...Advisory / Atomic model / Data collection / Derived calculations / Structure summary
Category: atom_site / chem_comp ...atom_site / chem_comp / entity / pdbx_branch_scheme / pdbx_chem_comp_identifier / pdbx_entity_branch / pdbx_entity_branch_descriptor / pdbx_entity_branch_link / pdbx_entity_branch_list / pdbx_entity_nonpoly / pdbx_nonpoly_scheme / pdbx_struct_assembly_gen / pdbx_struct_special_symmetry / pdbx_unobs_or_zero_occ_atoms / struct_asym / struct_conn / struct_site / struct_site_gen
Item: _atom_site.B_iso_or_equiv / _atom_site.Cartn_x ..._atom_site.B_iso_or_equiv / _atom_site.Cartn_x / _atom_site.Cartn_y / _atom_site.Cartn_z / _atom_site.auth_asym_id / _atom_site.auth_atom_id / _atom_site.auth_comp_id / _atom_site.auth_seq_id / _atom_site.label_asym_id / _atom_site.label_atom_id / _atom_site.label_comp_id / _atom_site.label_entity_id / _atom_site.occupancy / _atom_site.type_symbol / _chem_comp.name / _chem_comp.type / _pdbx_entity_nonpoly.entity_id / _pdbx_entity_nonpoly.name / _pdbx_struct_assembly_gen.asym_id_list / _pdbx_struct_special_symmetry.label_asym_id / _pdbx_unobs_or_zero_occ_atoms.label_asym_id / _struct_conn.pdbx_role / _struct_conn.ptnr1_auth_asym_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr2_auth_asym_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id
Description: Carbohydrate remediation / Provider: repository / Type: Remediation
Revision 2.1Jan 24, 2024Group: Data collection / Database references ...Data collection / Database references / Refinement description / Structure summary
Category: chem_comp / chem_comp_atom ...chem_comp / chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _chem_comp.pdbx_synonyms / _database_2.pdbx_DOI / _database_2.pdbx_database_accession
Revision 2.2Nov 6, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature

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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)116,11746
Polymers111,2802
Non-polymers4,83744
Water17,439968
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration, single peak in gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area8450 Å2
ΔGint-170 kcal/mol
Surface area37090 Å2
MethodPISA
Unit cell
Length a, b, c (Å)110.383, 285.152, 91.903
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
11B-749-

HOH

21B-1029-

HOH

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Components

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Protein , 1 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.: 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

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Sugars , 2 types, 3 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.: 2
Source method: isolated from a genetically manipulated 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
#6: 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 genetically manipulated 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 , 4 types, 1009 molecules

#3: Chemical
ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 15 / Source method: obtained synthetically / Formula: SO4
#4: Chemical...
ChemComp-ACT / ACETATE ION


Mass: 59.044 Da / Num. of mol.: 24 / Source method: obtained synthetically / Formula: C2H3O2
#5: Chemical ChemComp-HK2 / (1~{S},3~{S},4~{R},6~{R})-2,3,4,6-tetrakis(oxidanyl)-5-[[4-[3-(4-phenylphenoxy)propyl]-1,2,3-triazol-1-yl]methyl]cyclohexan-1-olate


Mass: 454.496 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C24H28N3O6
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 968 / Source method: isolated from a natural source / Formula: H2O

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Details

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: 3.25 Å3/Da / Density % sol: 62.15 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 4.6
Details: Ammonium sulfate, Gaunidine Hydrochloride, Potassium chloride, Sodium acetate (pH 4.6)

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I24 / Wavelength: 0.97718 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Jul 8, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97718 Å / Relative weight: 1
ReflectionResolution: 1.63→72.13 Å / Num. obs: 179767 / % possible obs: 99.92 % / Redundancy: 6.49 % / Net I/σ(I): 8.83
Reflection shellResolution: 1.63→1.66 Å / Mean I/σ(I) obs: 1.08 / Rpim(I) all: 1.135 / % possible all: 98.79

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Processing

Software
NameVersionClassification
REFMAC5.8.0238refinement
xia2data reduction
Aimlessdata scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2NT0

2nt0


Resolution: 1.63→72.13 Å / Cor.coef. Fo:Fc: 0.971 / Cor.coef. Fo:Fc free: 0.958 / SU B: 2.886 / SU ML: 0.086 / Cross valid method: THROUGHOUT / ESU R: 0.079 / ESU R Free: 0.081 / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.21207 8920 5 %RANDOM
Rwork0.18174 ---
obs0.18323 170813 99.88 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso mean: 25.693 Å2
Baniso -1Baniso -2Baniso -3
1-3.49 Å20 Å2-0 Å2
2---1.15 Å20 Å2
3----2.34 Å2
Refinement stepCycle: 1 / Resolution: 1.63→72.13 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7739 0 277 968 8984
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0120.0138384
X-RAY DIFFRACTIONr_bond_other_d0.0010.0177463
X-RAY DIFFRACTIONr_angle_refined_deg1.6581.6611462
X-RAY DIFFRACTIONr_angle_other_deg1.4181.58417316
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.49351041
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.99521.935398
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.84915.061260
X-RAY DIFFRACTIONr_dihedral_angle_4_deg20.0011543
X-RAY DIFFRACTIONr_chiral_restr0.0890.21077
X-RAY DIFFRACTIONr_gen_planes_refined0.010.029378
X-RAY DIFFRACTIONr_gen_planes_other0.0020.021791
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it2.3112.4534052
X-RAY DIFFRACTIONr_mcbond_other2.2632.4384035
X-RAY DIFFRACTIONr_mcangle_it3.1453.6355056
X-RAY DIFFRACTIONr_mcangle_other3.1483.6365057
X-RAY DIFFRACTIONr_scbond_it3.3682.8834332
X-RAY DIFFRACTIONr_scbond_other3.3682.8844333
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other5.0384.2056407
X-RAY DIFFRACTIONr_long_range_B_refined6.73930.5639554
X-RAY DIFFRACTIONr_long_range_B_other6.73830.5699555
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.63→1.672 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.383 613 -
Rwork0.381 12529 -
obs--99.21 %

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