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- PDB-6q6l: Crystal structure of recombinant human beta-glucocerebrosidase in... -

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Basic information

Entry
Database: PDB / ID: 6q6l
TitleCrystal structure of recombinant human beta-glucocerebrosidase in complex with adamantyl-cyclophellitol inhibitor (ME656)
ComponentsGlucosylceramidase
KeywordsHYDROLASE / RETAINING BETA-GLUCOSIDASE
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 / response to pH / Hydrolases; Glycosylases; Glycosidases, i.e. enzymes that hydrolyse O- and S-glycosyl compounds / 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 / cholesterol metabolic process / respiratory electron transport chain / cellular response to starvation / lysosomal lumen / negative regulation of MAP kinase activity / 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 / 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 / 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-RJR / Lysosomal acid glucosylceramidase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.81 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 2.0Jul 29, 2020Group: Atomic model / Data collection ...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 / 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_struct_assembly_gen.asym_id_list / _pdbx_struct_special_symmetry.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

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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)116,62650
Polymers111,2802
Non-polymers5,34648
Water16,862936
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 area10070 Å2
ΔGint-235 kcal/mol
Surface area36660 Å2
MethodPISA
Unit cell
Length a, b, c (Å)110.214, 285.131, 92.003
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-990-

HOH

21A-1094-

HOH

31B-754-

HOH

41B-1011-

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 , 3 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.: 1
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
#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 genetically manipulated 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
#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 / N-Acetylglucosamine


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, 981 molecules

#4: Chemical
ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 19 / Source method: obtained synthetically / Formula: SO4
#5: Chemical...
ChemComp-ACT / ACETATE ION / Acetate


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


Mass: 435.557 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C23H37N3O5 / Feature type: SUBJECT OF INVESTIGATION
#8: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 936 / Source method: isolated from a natural source / Formula: H2O

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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: 62.13 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 4.6
Details: Ammonium sulfate, Guanidine 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: 1.81→72.08 Å / Num. obs: 131678 / % possible obs: 99.95 % / Redundancy: 6.53 % / Rmerge(I) obs: 0.132 / Net I/σ(I): 7.71
Reflection shellResolution: 1.81→1.84 Å / Mean I/σ(I) obs: 1.02

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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: 1.81→72.08 Å / Cor.coef. Fo:Fc: 0.968 / Cor.coef. Fo:Fc free: 0.953 / SU B: 3.551 / SU ML: 0.099 / Cross valid method: THROUGHOUT / ESU R: 0.105 / ESU R Free: 0.105 / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.20977 6547 5 %RANDOM
Rwork0.1764 ---
obs0.17804 125104 99.89 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso mean: 27.68 Å2
Baniso -1Baniso -2Baniso -3
1-3.28 Å20 Å2-0 Å2
2---0.98 Å20 Å2
3----2.3 Å2
Refinement stepCycle: 1 / Resolution: 1.81→72.08 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7830 0 334 936 9100
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.010.0138531
X-RAY DIFFRACTIONr_bond_other_d0.0010.0177602
X-RAY DIFFRACTIONr_angle_refined_deg1.6271.66711670
X-RAY DIFFRACTIONr_angle_other_deg1.3651.59317655
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.59351024
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.69321.867407
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.19215.0081269
X-RAY DIFFRACTIONr_dihedral_angle_4_deg18.191544
X-RAY DIFFRACTIONr_chiral_restr0.0870.21095
X-RAY DIFFRACTIONr_gen_planes_refined0.010.029457
X-RAY DIFFRACTIONr_gen_planes_other0.0030.021827
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_it2.2452.6454064
X-RAY DIFFRACTIONr_mcbond_other2.1652.634042
X-RAY DIFFRACTIONr_mcangle_it3.0783.9355071
X-RAY DIFFRACTIONr_mcangle_other3.0793.9365072
X-RAY DIFFRACTIONr_scbond_it3.1763.1264467
X-RAY DIFFRACTIONr_scbond_other3.1763.1264468
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other4.7354.5816600
X-RAY DIFFRACTIONr_long_range_B_refined6.4933.1519677
X-RAY DIFFRACTIONr_long_range_B_other6.49133.1589678
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.81→1.857 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.329 467 -
Rwork0.327 9082 -
obs--98.98 %

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