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

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Basic information

Entry
Database: PDB / ID: 9fad
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 / 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 / scavenger receptor binding / glucosylceramide catabolic process / regulation of lysosomal protein catabolic process / autophagosome organization / glucosylceramidase activity / microglial cell proliferation / sphingosine biosynthetic process / 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 / antigen processing and presentation / 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 / positive regulation of protein dephosphorylation / cell maturation / cellular response to starvation / cholesterol metabolic process / respiratory electron transport chain / 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
: / : / Lysosomal acid glucosylceramidase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 1.8 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

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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)62,4467
Polymers61,1951
Non-polymers1,2516
Water8,701483
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1470 Å2
ΔGint-7 kcal/mol
Surface area18980 Å2
Unit cell
Length a, b, c (Å)52.861, 74.205, 68.539
Angle α, β, γ (deg.)90.00, 102.63, 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: 61194.504 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, 2 molecules

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


Type: oligosaccharide / Mass: 627.594 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DGlcpNAcb1-4DGlcpNAcb1-4DGlcpNAcb1-ROHGlycam Condensed SequenceGMML 1.0
WURCS=2.0/1,3,2/[a2122h-1b_1-5_2*NCC/3=O]/1-1-1/a4-b1_b4-c1WURCSPDB2Glycan 1.1.0
[][D-1-deoxy-GlcpNAc]{[(4+1)][b-D-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 , 4 types, 487 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-A1IBD / ~{N}-[(2~{S})-2-azanylpropyl]-4-methyl-benzenesulfonamide


Mass: 228.311 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C10H16N2O2S / Feature type: SUBJECT OF INVESTIGATION
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 483 / 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: 2.14 Å3/Da / Density % sol: 42.62 %
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 / Wavelength: 0.9795 Å
DetectorType: DECTRIS EIGER2 XE 16M / Detector: PIXEL / Date: Feb 11, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9795 Å / Relative weight: 1
ReflectionResolution: 1.537→51.64 Å / Num. obs: 44614 / % possible obs: 90.7 % / Redundancy: 3.3 % / Rrim(I) all: 0.112 / Net I/σ(I): 8.8
Reflection shellResolution: 1.537→1.729 Å / Num. unique obs: 2231 / Rrim(I) all: 0.751

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Processing

Software
NameVersionClassification
REFMAC5.8.0232refinement
XDSdata reduction
Aimlessdata scaling
REFMACphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 1.8→51.64 Å / Cor.coef. Fo:Fc: 0.954 / Cor.coef. Fo:Fc free: 0.923 / SU B: 7.791 / SU ML: 0.119 / Cross valid method: THROUGHOUT / ESU R: 0.161 / ESU R Free: 0.148 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.2202 1890 4.8 %RANDOM
Rwork0.17316 ---
obs0.17539 37811 82.77 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 19.543 Å2
Baniso -1Baniso -2Baniso -3
1-1.21 Å20 Å2-0.14 Å2
2---0.02 Å20 Å2
3----1.02 Å2
Refinement stepCycle: 1 / Resolution: 1.8→51.64 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3932 0 78 483 4493
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0090.0154133
X-RAY DIFFRACTIONr_bond_other_d0.0010.0173640
X-RAY DIFFRACTIONr_angle_refined_deg1.441.7825642
X-RAY DIFFRACTIONr_angle_other_deg0.5031.7358523
X-RAY DIFFRACTIONr_dihedral_angle_1_deg8.7025.267505
X-RAY DIFFRACTIONr_dihedral_angle_2_deg33.32121.189185
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.82415.25621
X-RAY DIFFRACTIONr_dihedral_angle_4_deg13.7521522
X-RAY DIFFRACTIONr_chiral_restr0.0720.2536
X-RAY DIFFRACTIONr_gen_planes_refined0.0010.0214602
X-RAY DIFFRACTIONr_gen_planes_other00.02814
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_it0.6371.191987
X-RAY DIFFRACTIONr_mcbond_other0.6371.1911988
X-RAY DIFFRACTIONr_mcangle_it
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it1.7051.7362146
X-RAY DIFFRACTIONr_scbond_other1.7051.7382147
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other
X-RAY DIFFRACTIONr_long_range_B_refined4.2837.7314526
X-RAY DIFFRACTIONr_long_range_B_other4.187.3984484
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.8→1.847 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.275 78 -
Rwork0.267 1583 -
obs--47.23 %
Refinement TLS params.Method: refined / Origin x: -14.3858 Å / Origin y: 3.4396 Å / Origin z: -6.0453 Å
111213212223313233
T0.0048 Å2-0.0022 Å2-0.0218 Å2-0.0566 Å2-0.0013 Å2--0.1626 Å2
L0.8903 °20.1282 °2-0.2881 °2-0.4328 °2-0.0999 °2--1.18 °2
S0.0015 Å °0.0774 Å °0.0135 Å °-0.0222 Å °0.0035 Å °-0.0002 Å °-0.0115 Å °-0.1051 Å °-0.005 Å °

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