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- PDB-9fa3: Gcase in complex with small molecule inhibitor 1 -

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Basic information

Entry
Database: PDB / ID: 9fa3
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


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 / 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 dexamethasone / Association of TriC/CCT with target proteins during biosynthesis / response to testosterone / 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 / lysosomal lumen / cellular response to starvation / 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 / Glycoside hydrolase superfamily
Similarity search - Domain/homology
: / : / Lysosomal acid glucosylceramidase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 1.36 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 10, 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 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

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Assembly

Deposited unit
A: Lysosomal acid glucosylceramidase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)62,4158
Polymers61,1631
Non-polymers1,2527
Water7,746430
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1990 Å2
ΔGint-5 kcal/mol
Surface area18850 Å2
MethodPISA
Unit cell
Length a, b, c (Å)52.806, 74.744, 68.419
Angle α, β, γ (deg.)90.00, 102.56, 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.: 1
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.: 2 / 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 , 4 types, 434 molecules

#4: Chemical ChemComp-K / POTASSIUM ION


Mass: 39.098 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: K
#5: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: SO4
#6: Chemical ChemComp-A1IBC / ~{N}-(cyclopropylmethyl)benzenesulfonamide


Mass: 211.281 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C10H13NO2S / Feature type: SUBJECT OF INVESTIGATION
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 430 / 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: 2.15 Å3/Da / Density % sol: 42.92 %
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: ESRF / Beamline: ID29 / Wavelength: 0.97371 Å
DetectorType: DECTRIS PILATUS 6M-F / Detector: PIXEL / Date: Aug 30, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97371 Å / Relative weight: 1
ReflectionResolution: 1.36→51.6 Å / Num. obs: 69032 / % possible obs: 82 % / Redundancy: 3.1 % / Rrim(I) all: 0.074 / Net I/σ(I): 9.9
Reflection shellResolution: 1.368→1.494 Å / Num. unique obs: 3584 / Rrim(I) all: 0.791

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Processing

Software
NameVersionClassification
REFMAC5.8.0232refinement
XDSdata reduction
Aimlessdata scaling
REFMACphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 1.36→51.6 Å / Cor.coef. Fo:Fc: 0.969 / Cor.coef. Fo:Fc free: 0.957 / SU B: 3.138 / SU ML: 0.056 / Cross valid method: THROUGHOUT / ESU R: 0.082 / ESU R Free: 0.083 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.20472 3508 4.8 %RANDOM
Rwork0.17294 ---
obs0.17445 69032 64.53 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 20.663 Å2
Baniso -1Baniso -2Baniso -3
1-0.01 Å20 Å20.36 Å2
2---1.04 Å2-0 Å2
3---0.79 Å2
Refinement stepCycle: 1 / Resolution: 1.36→51.6 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3940 0 77 430 4447
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.010.0154219
X-RAY DIFFRACTIONr_bond_other_d0.0010.0173725
X-RAY DIFFRACTIONr_angle_refined_deg1.5221.7775780
X-RAY DIFFRACTIONr_angle_other_deg0.5191.7318740
X-RAY DIFFRACTIONr_dihedral_angle_1_deg8.5485.227529
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.07521.105190
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.51715.28644
X-RAY DIFFRACTIONr_dihedral_angle_4_deg17.4971523
X-RAY DIFFRACTIONr_chiral_restr0.0790.2548
X-RAY DIFFRACTIONr_gen_planes_refined0.0010.0214714
X-RAY DIFFRACTIONr_gen_planes_other00.02833
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_it1.1141.932015
X-RAY DIFFRACTIONr_mcbond_other1.1141.9322016
X-RAY DIFFRACTIONr_mcangle_it
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it2.3932.7412204
X-RAY DIFFRACTIONr_scbond_other2.3922.7422205
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other
X-RAY DIFFRACTIONr_long_range_B_refined4.94911.9954658
X-RAY DIFFRACTIONr_long_range_B_other4.87911.7314628
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.36→1.39 Å
RfactorNum. reflection% reflection
Rfree0.285 25 -
Rwork0.374 496 -
obs--6.28 %
Refinement TLS params.Method: refined / Origin x: -14.4583 Å / Origin y: 3.4469 Å / Origin z: -5.8493 Å
111213212223313233
T0.0347 Å20.0008 Å2-0.0152 Å2-0.0432 Å2-0.0021 Å2--0.009 Å2
L1.1702 °20.1961 °2-0.2564 °2-0.3946 °2-0.1129 °2--1.1163 °2
S-0.0011 Å °0.0273 Å °-0.0412 Å °-0.0303 Å °-0.0128 Å °-0.0094 Å °-0.0076 Å °-0.0466 Å °0.0139 Å °

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