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- PDB-9fb2: Gcase in complex with small molecule inhibitor 1 -

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Basic information

Entry
Database: PDB / ID: 9fb2
TitleGcase in complex with small molecule inhibitor 1
ComponentsLysosomal acid glucosylceramidase
KeywordsLIPID BINDING PROTEIN / Glycosidase / cholesterol metabolism / steroid metabolism / glycosyl transferase
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
: / : / DI(HYDROXYETHYL)ETHER / Lysosomal acid glucosylceramidase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 1.14 Å
AuthorsTisi, D. / Cleasby, A.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: J.Med.Chem. / Year: 2024
Title: Fragment-Based Discovery of a Series of Allosteric-Binding Site Modulators of beta-Glucocerebrosidase.
Authors: Palmer, N. / Agnew, C. / Benn, C. / Buffham, W.J. / Castro, J.N. / Chessari, G. / Clark, M. / Cons, B.D. / Coyle, J.E. / Dawson, L.A. / Hamlett, C.C.F. / Hodson, C. / Holding, F. / Johnson, ...Authors: Palmer, N. / Agnew, C. / Benn, C. / Buffham, W.J. / Castro, J.N. / Chessari, G. / Clark, M. / Cons, B.D. / Coyle, J.E. / Dawson, L.A. / Hamlett, C.C.F. / Hodson, C. / Holding, F. / Johnson, C.N. / Liebeschuetz, J.W. / Mahajan, P. / McCarthy, J.M. / Murray, C.W. / O'Reilly, M. / Peakman, T. / Price, A. / Rapti, M. / Reeks, J. / Schopf, P. / St-Denis, J.D. / Valenzano, C. / Wallis, N.G. / Walser, R. / Weir, H. / Wilsher, N.E. / Woodhead, A. / Bento, C.F. / Tisi, D.
History
DepositionMay 11, 2024Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jul 3, 2024Provider: repository / Type: Initial release
Revision 1.1Jul 24, 2024Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
Revision 1.2Oct 23, 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
A: Lysosomal acid glucosylceramidase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)63,29615
Polymers61,1631
Non-polymers2,13314
Water12,250680
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3840 Å2
ΔGint15 kcal/mol
Surface area18940 Å2
Unit cell
Length a, b, c (Å)52.699, 74.450, 68.192
Angle α, β, γ (deg.)90.00, 102.81, 90.00
Int Tables number4
Space group name H-MP1211

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Components

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Protein , 1 types, 1 molecules A

#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 / Beta-glucosylceramidase 1 / Cholesterol glucosyltransferase / SGTase / Cholesteryl-beta-glucosidase / D-glucosyl-N-acylsphingosine glucohydrolase / Glucosylceramidase beta 1 / Imiglucerase / Lysosomal cholesterol glycosyltransferase / Lysosomal galactosylceramidase / Lysosomal glycosylceramidase


Mass: 61162.504 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GBA1, GBA, GC, GLUC / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P04062, glucosylceramidase, Transferases; Glycosyltransferases; Hexosyltransferases, Hydrolases; Glycosylases; Glycosidases, i.e. enzymes that hydrolyse O- and S-glycosyl ...References: UniProt: P04062, glucosylceramidase, Transferases; Glycosyltransferases; Hexosyltransferases, Hydrolases; Glycosylases; Glycosidases, i.e. enzymes that hydrolyse O- and S-glycosyl compounds, galactosylceramidase

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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-ROHGlycam 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
[][D-1-deoxy-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{}}LINUCSPDB-CARE
#3: 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: 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 , 6 types, 691 molecules

#4: Chemical ChemComp-K / POTASSIUM ION


Mass: 39.098 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: K
#5: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: C2H6O2
#6: Chemical ChemComp-PEG / DI(HYDROXYETHYL)ETHER


Mass: 106.120 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C4H10O3
#7: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: SO4
#8: Chemical ChemComp-A1IBO / ~{N}-[(2~{R})-2-azanyl-2-(3-prop-1-en-2-ylphenyl)ethyl]-3,5-bis(fluoranyl)-~{N}-methyl-benzenesulfonamide


Mass: 366.425 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C18H20F2N2O2S / Feature type: SUBJECT OF INVESTIGATION
#9: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 680 / 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: 2.13 Å3/Da / Density % sol: 42.33 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / Details: 0.1M KSCN 25% PEG 3350

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I04-1 / Wavelength: 0.9126 Å
DetectorType: DECTRIS EIGER2 XE 9M / Detector: PIXEL / Date: Mar 3, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9126 Å / Relative weight: 1
ReflectionResolution: 1.14→51.44 Å / Num. obs: 127494 / % possible obs: 93.8 % / Redundancy: 3 % / Rrim(I) all: 0.054 / Net I/σ(I): 10.1
Reflection shellResolution: 1.165→1.268 Å / Num. unique obs: 6375 / Rrim(I) all: 0.607 / % possible all: 65.4

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Processing

Software
NameVersionClassification
REFMAC5.8.0232refinement
XDSdata reduction
Aimlessdata scaling
REFMACphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 1.14→51.44 Å / Cor.coef. Fo:Fc: 0.974 / Cor.coef. Fo:Fc free: 0.969 / SU B: 1.456 / SU ML: 0.031 / Cross valid method: THROUGHOUT / ESU R: 0.043 / ESU R Free: 0.043 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.1724 6555 4.9 %RANDOM
Rwork0.15666 ---
obs0.15743 127355 72.09 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 17.029 Å2
Baniso -1Baniso -2Baniso -3
1-0.35 Å2-0 Å20 Å2
2---0.85 Å2-0 Å2
3---0.45 Å2
Refinement stepCycle: 1 / Resolution: 1.14→51.44 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3950 0 136 680 4766
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.010.0154283
X-RAY DIFFRACTIONr_bond_other_d0.0010.0173791
X-RAY DIFFRACTIONr_angle_refined_deg1.5961.7865849
X-RAY DIFFRACTIONr_angle_other_deg0.5441.7488887
X-RAY DIFFRACTIONr_dihedral_angle_1_deg11.0985.393534
X-RAY DIFFRACTIONr_dihedral_angle_2_deg33.7720.876194
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.44615.341660
X-RAY DIFFRACTIONr_dihedral_angle_4_deg13.4151525
X-RAY DIFFRACTIONr_chiral_restr0.0870.2552
X-RAY DIFFRACTIONr_gen_planes_refined0.0020.0214765
X-RAY DIFFRACTIONr_gen_planes_other00.02839
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_it0.8881.4792026
X-RAY DIFFRACTIONr_mcbond_other0.8881.4812027
X-RAY DIFFRACTIONr_mcangle_it
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it2.1492.3222257
X-RAY DIFFRACTIONr_scbond_other2.1492.3222258
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other
X-RAY DIFFRACTIONr_long_range_B_refined4.72710.1034857
X-RAY DIFFRACTIONr_long_range_B_other4.5639.4374774
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.142→1.171 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.387 25 -
Rwork0.355 451 -
obs--3.47 %
Refinement TLS params.Method: refined / Origin x: -14.4949 Å / Origin y: 2.9764 Å / Origin z: -5.8149 Å
111213212223313233
T0.0012 Å20.001 Å20.0001 Å2-0.0272 Å2-0.004 Å2--0.0014 Å2
L0.9235 °20.0818 °2-0.1733 °2-0.3036 °2-0.0464 °2--0.921 °2
S0.0047 Å °0.0462 Å °-0.0204 Å °-0.0157 Å °-0.0145 Å °-0.0095 Å °-0.005 Å °-0.0645 Å °0.0098 Å °

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