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- PDB-7nwv: Structure of recombinant human beta-glucocerebrosidase in complex... -

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Basic information

Entry
Database: PDB / ID: 7nwv
TitleStructure of recombinant human beta-glucocerebrosidase in complex with BODIPY Tagged Cyclophellitol activity based probe
ComponentsLysosomal acid glucosylceramidase
KeywordsHYDROLASE / beta-glucocerebrosidase / lysosomal glycoside hydrolase / GH30 / Cyclophellitol epoxide / activity based probe / Complex
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 / positive regulation of autophagy of mitochondrion in response to mitochondrial depolarization / galactosylceramidase / termination of signal transduction / galactosylceramidase activity / 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 / positive regulation of autophagy of mitochondrion in response to mitochondrial depolarization / galactosylceramidase / termination of signal transduction / galactosylceramidase activity / lymphocyte migration / glucosylceramidase / glucosylceramide catabolic process / scavenger receptor binding / regulation of lysosomal protein catabolic process / autophagosome organization / sphingosine biosynthetic process / glucosylceramidase activity / microglial cell proliferation / glucosyltransferase activity / regulation of TOR signaling / ceramide biosynthetic process / lipid storage / response to thyroid hormone / 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 testosterone / response to dexamethasone / Association of TriC/CCT with target proteins during biosynthesis / negative regulation of interleukin-6 production / antigen processing and presentation / homeostasis of number of cells / regulation of macroautophagy / establishment of skin barrier / negative regulation of protein-containing complex assembly / positive regulation of protein dephosphorylation / cell maturation / respiratory electron transport chain / cellular response to starvation / cholesterol metabolic process / lysosomal lumen / negative regulation of MAP kinase activity / 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 / 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 / Glycoside hydrolase superfamily
Similarity search - Domain/homology
Chem-UUE / Chem-UUH / Lysosomal acid glucosylceramidase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.86 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: Chem Sci / Year: 2023
Title: Fluorescence polarisation activity-based protein profiling for the identification of deoxynojirimycin-type inhibitors selective for lysosomal retaining alpha- and beta-glucosidases.
Authors: van der Gracht, D. / Rowland, R.J. / Roig-Zamboni, V. / Ferraz, M.J. / Louwerse, M. / Geurink, P.P. / Aerts, J.M.F.G. / Sulzenbacher, G. / Davies, G.J. / Overkleeft, H.S. / Artola, M.
History
DepositionMar 17, 2021Deposition site: PDBE / Processing site: PDBE
Revision 1.0Mar 30, 2022Provider: repository / Type: Initial release
Revision 1.1Sep 13, 2023Group: Data collection / Database references / Derived calculations
Category: atom_type / chem_comp_atom ...atom_type / chem_comp_atom / chem_comp_bond / citation / citation_author
Item: _atom_type.pdbx_N_electrons / _atom_type.pdbx_scat_Z ..._atom_type.pdbx_N_electrons / _atom_type.pdbx_scat_Z / _citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Jan 31, 2024Group: Refinement description / Category: pdbx_initial_refinement_model

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)117,52653
Polymers111,3182
Non-polymers6,20851
Water13,403744
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration, Single peak in gel filtration and single band by SDS-PAGE
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area11720 Å2
ΔGint-14 kcal/mol
Surface area35490 Å2
MethodPISA
Unit cell
Length a, b, c (Å)52.956, 158.420, 68.238
Angle α, β, γ (deg.)90.000, 102.147, 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: Human beta-glucocerebrosidase without 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, steryl-beta-glucosidase

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Sugars , 2 types, 5 molecules

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


Type: oligosaccharide / Mass: 570.542 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
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
[][D-1-deoxy-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-Manp]{}}}LINUCSPDB-CARE
#5: 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.: 3 / 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 , 5 types, 790 molecules

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


Mass: 96.063 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: SO4
#4: Chemical ChemComp-UUH / (1~{S},2~{R},3~{R},4~{S},5~{S})-4-[[4-[4-[2,2-bis(fluoranyl)-4,6,10,12-tetramethyl-3-aza-1-azonia-2-boranuidatricyclo[7.3.0.0^{3,7}]dodeca-1(12),4,6,8,10-pentaen-8-yl]butyl]-1,2,3-triazol-1-yl]methyl]cyclohexane-1,2,3,5-tetrol


Mass: 531.403 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C26H36BF2N5O4 / Feature type: SUBJECT OF INVESTIGATION
#6: Chemical...
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL / Ethylene glycol


Mass: 62.068 Da / Num. of mol.: 35 / Source method: obtained synthetically / Formula: C2H6O2
#7: Chemical ChemComp-UUE / 8-[4-(1-ethyl-1,2,3-triazol-4-yl)butyl]-2,2-bis(fluoranyl)-4,6,10,12-tetramethyl-3-aza-1-azonia-2-boranuidatricyclo[7.3.0.0^{3,7}]dodeca-1(12),4,6,8,10-pentaene


Mass: 399.288 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H28BF2N5 / Feature type: SUBJECT OF INVESTIGATION
#8: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 744 / 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: 2.51 Å3/Da / Density % sol: 51.07 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 7
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: I03 / Wavelength: 0.976254 Å
DetectorType: DECTRIS EIGER2 XE 16M / Detector: PIXEL / Date: Mar 4, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.976254 Å / Relative weight: 1
ReflectionResolution: 1.86→158.42 Å / Num. obs: 91928 / % possible obs: 100 % / Redundancy: 6.9 % / CC1/2: 0.996 / Rmerge(I) obs: 0.119 / Rrim(I) all: 0.129 / Net I/σ(I): 9.1
Reflection shellResolution: 1.86→1.89 Å / Rmerge(I) obs: 0.843 / Mean I/σ(I) obs: 2 / Num. unique obs: 32337 / CC1/2: 0.859 / Rrim(I) all: 0.913

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Processing

Software
NameVersionClassification
REFMAC5.8.0258refinement
xia2data reduction
Aimlessdata scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6TJK

6tjk


Resolution: 1.86→66.8 Å / Cor.coef. Fo:Fc: 0.954 / Cor.coef. Fo:Fc free: 0.919 / WRfactor Rfree: 0.223 / WRfactor Rwork: 0.169 / SU B: 3.734 / SU ML: 0.109 / Average fsc free: 0.8856 / Average fsc work: 0.9035 / Cross valid method: FREE R-VALUE / ESU R: 0.141 / ESU R Free: 0.141
Details: Hydrogens have been added in their riding positions
RfactorNum. reflection% reflection
Rfree0.2318 4665 5.077 %
Rwork0.1769 87211 -
all0.18 --
obs-91876 99.94 %
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: 24.294 Å2
Baniso -1Baniso -2Baniso -3
1-0.347 Å20 Å20.087 Å2
2--1.848 Å20 Å2
3----2.043 Å2
Refinement stepCycle: LAST / Resolution: 1.86→66.8 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7819 0 384 744 8947
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0090.0138529
X-RAY DIFFRACTIONr_bond_other_d0.0010.0177717
X-RAY DIFFRACTIONr_angle_refined_deg1.571.67111599
X-RAY DIFFRACTIONr_angle_other_deg1.3291.58517892
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.47851049
X-RAY DIFFRACTIONr_dihedral_angle_other_1_deg37.4532011
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.28621.691408
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.19615.0821285
X-RAY DIFFRACTIONr_dihedral_angle_4_deg20.0721548
X-RAY DIFFRACTIONr_chiral_restr0.080.21090
X-RAY DIFFRACTIONr_gen_planes_refined0.0080.029376
X-RAY DIFFRACTIONr_gen_planes_other0.0010.021820
X-RAY DIFFRACTIONr_nbd_refined0.2050.21759
X-RAY DIFFRACTIONr_symmetry_nbd_other0.1870.27509
X-RAY DIFFRACTIONr_nbtor_refined0.1690.23980
X-RAY DIFFRACTIONr_symmetry_nbtor_other0.0920.23582
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1620.2609
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_other0.0720.24
X-RAY DIFFRACTIONr_symmetry_nbd_refined0.1920.221
X-RAY DIFFRACTIONr_nbd_other0.240.277
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_refined0.1620.224
X-RAY DIFFRACTIONr_mcbond_it1.7222.3834029
X-RAY DIFFRACTIONr_mcbond_other1.7222.3834028
X-RAY DIFFRACTIONr_mcangle_it2.3563.5685052
X-RAY DIFFRACTIONr_mcangle_other2.3553.5685053
X-RAY DIFFRACTIONr_scbond_it2.4042.7244500
X-RAY DIFFRACTIONr_scbond_other2.4032.7254501
X-RAY DIFFRACTIONr_scangle_it3.4373.9736547
X-RAY DIFFRACTIONr_scangle_other3.4373.9746548
X-RAY DIFFRACTIONr_lrange_it4.94929.0999643
X-RAY DIFFRACTIONr_lrange_other4.94929.1059644
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.86-1.9080.2753290.2586456X-RAY DIFFRACTION99.8675
1.908-1.9610.3143510.2596289X-RAY DIFFRACTION99.9398
1.961-2.0170.2463370.1986070X-RAY DIFFRACTION100
2.017-2.0790.2733220.2235912X-RAY DIFFRACTION99.9359
2.079-2.1480.2363010.1865753X-RAY DIFFRACTION100
2.148-2.2230.233110.1765556X-RAY DIFFRACTION100
2.223-2.3070.292780.2255363X-RAY DIFFRACTION99.9468
2.307-2.4010.2032870.1595152X-RAY DIFFRACTION99.9632
2.401-2.5080.2212480.1634969X-RAY DIFFRACTION100
2.508-2.630.2222480.1554756X-RAY DIFFRACTION100
2.63-2.7720.232260.1564511X-RAY DIFFRACTION99.9789
2.772-2.9410.2282330.1594280X-RAY DIFFRACTION100
2.941-3.1430.2312310.1683973X-RAY DIFFRACTION99.9762
3.143-3.3950.2312150.1763708X-RAY DIFFRACTION100
3.395-3.7190.2131670.1783434X-RAY DIFFRACTION100
3.719-4.1580.1981560.1543134X-RAY DIFFRACTION100
4.158-4.8010.2061190.1392789X-RAY DIFFRACTION99.9313
4.801-5.8780.2111340.1592321X-RAY DIFFRACTION100
5.878-8.3070.2571120.1971777X-RAY DIFFRACTION100
8.307-66.80.236600.2041008X-RAY DIFFRACTION99.6269

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