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- PDB-5lvx: Crystal structure of glucocerebrosidase with an inhibitory quinaz... -

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Basic information

Entry
Database: PDB / ID: 5lvx
TitleCrystal structure of glucocerebrosidase with an inhibitory quinazoline modulator
ComponentsGlucosylceramidase
KeywordsHYDROLASE / GCASE / GLYCOPROTEIN / GLYCOSIDASE / GLUCOSYLCERAMIDASE / PROT / PROTEROS BIOSTRUCTURES GMBH
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 / microglia differentiation / response to thyroid hormone / 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 / respiratory electron transport chain / 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 / 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
Chem-79B / Chem-7E4 / PHOSPHATE ION / Lysosomal acid glucosylceramidase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / OTHER / Resolution: 2.2 Å
AuthorsZheng, J. / Chen, L. / Skinner, O.S. / Lansbury, P. / Skerlj, R. / Mrosek, M. / Heunisch, U. / Krapp, S. / Weigand, S. / Charrow, J. ...Zheng, J. / Chen, L. / Skinner, O.S. / Lansbury, P. / Skerlj, R. / Mrosek, M. / Heunisch, U. / Krapp, S. / Weigand, S. / Charrow, J. / Schwake, M. / Kelleher, N.L. / Silverman, R.B. / Krainc, D.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of HealthR01NS076054 United States
CitationJournal: J. Am. Chem. Soc. / Year: 2018
Title: beta-Glucocerebrosidase Modulators Promote Dimerization of beta-Glucocerebrosidase and Reveal an Allosteric Binding Site.
Authors: Zheng, J. / Chen, L. / Skinner, O.S. / Ysselstein, D. / Remis, J. / Lansbury, P. / Skerlj, R. / Mrosek, M. / Heunisch, U. / Krapp, S. / Charrow, J. / Schwake, M. / Kelleher, N.L. / Silverman, R.B. / Krainc, D.
History
DepositionSep 14, 2016Deposition site: PDBE / Processing site: PDBE
Revision 1.0Oct 25, 2017Provider: repository / Type: Initial release
Revision 1.1Apr 25, 2018Group: Data collection / Category: reflns / reflns_shell
Item: _reflns.pdbx_Rmerge_I_obs / _reflns_shell.Rmerge_I_obs
Revision 1.2May 9, 2018Group: Data collection / Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.3May 16, 2018Group: Data collection / Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.4May 23, 2018Group: Data collection / Category: diffrn_detector / Item: _diffrn_detector.pdbx_collection_date
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 / diffrn_radiation_wavelength / 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_mod_residue / 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_mod_residue.auth_asym_id / _pdbx_struct_mod_residue.auth_seq_id / _pdbx_struct_mod_residue.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

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Glucosylceramidase
B: Glucosylceramidase
C: Glucosylceramidase
D: Glucosylceramidase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)230,62935
Polymers222,6374
Non-polymers7,99331
Water12,268681
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area13670 Å2
ΔGint-75 kcal/mol
Surface area71320 Å2
MethodPISA
Unit cell
Length a, b, c (Å)94.910, 132.281, 103.085
Angle α, β, γ (deg.)90.00, 95.26, 90.00
Int Tables number4
Space group name H-MP1211
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11A
21B
12A
22C
13A
23D
14B
24C
15B
25D
16C
26D

NCS domain segments:
Dom-IDComponent-IDEns-IDRefine codeAuth asym-IDAuth seq-ID
1010A1 - 497
2010B1 - 497
1020A1 - 495
2020C1 - 495
1030A1 - 497
2030D1 - 497
1040B1 - 495
2040C1 - 495
1050B1 - 497
2050D1 - 497
1060C1 - 495
2060D1 - 495

NCS ensembles :
ID
1
2
3
4
5
6

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Components

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Protein , 1 types, 4 molecules ABCD

#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: 55659.219 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GBA, GC, GLUC / Cell line (production host): HT1080 / Production host: Homo sapiens (human) / References: UniProt: P04062, glucosylceramidase

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Sugars , 4 types, 6 molecules

#2: Polysaccharide alpha-D-mannopyranose-(1-2)-alpha-D-mannopyranose-(1-2)-alpha-D-mannopyranose-(1-3)-beta-D- ...alpha-D-mannopyranose-(1-2)-alpha-D-mannopyranose-(1-2)-alpha-D-mannopyranose-(1-3)-beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 1072.964 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DManpa1-2DManpa1-2DManpa1-3DManpb1-4DGlcpNAcb1-4DGlcpNAcb1-Glycam Condensed SequenceGMML 1.0
WURCS=2.0/3,6,5/[a2122h-1b_1-5_2*NCC/3=O][a1122h-1b_1-5][a1122h-1a_1-5]/1-1-2-3-3-3/a4-b1_b4-c1_c3-d1_d2-e1_e2-f1WURCSPDB2Glycan 1.1.0
[]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-Manp]{[(3+1)][a-D-Manp]{[(2+1)][a-D-Manp]{[(2+1)][a-D-Manp]{}}}}}}}LINUCSPDB-CARE
#3: 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
#4: Polysaccharide alpha-D-mannopyranose-(1-3)-[alpha-D-mannopyranose-(1-6)]beta-D-mannopyranose-(1-4)-2-acetamido-2- ...alpha-D-mannopyranose-(1-3)-[alpha-D-mannopyranose-(1-6)]beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 910.823 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DManpa1-3[DManpa1-6]DManpb1-4DGlcpNAcb1-4DGlcpNAcb1-Glycam Condensed SequenceGMML 1.0
WURCS=2.0/3,5,4/[a2122h-1b_1-5_2*NCC/3=O][a1122h-1b_1-5][a1122h-1a_1-5]/1-1-2-3-3/a4-b1_b4-c1_c3-d1_c6-e1WURCSPDB2Glycan 1.1.0
[]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-Manp]{[(3+1)][a-D-Manp]{}[(6+1)][a-D-Manp]{}}}}}LINUCSPDB-CARE
#7: Sugar ChemComp-NAG / 2-acetamido-2-deoxy-beta-D-glucopyranose


Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 2
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, 706 molecules

#5: Chemical ChemComp-79B / 11-[(2~{R})-2-[(2-pyridin-3-ylquinazolin-4-yl)amino]-2,3-dihydro-1~{H}-inden-5-yl]undec-10-ynoic acid


Mass: 518.649 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C33H34N4O2
#6: Chemical...
ChemComp-PO4 / PHOSPHATE ION


Mass: 94.971 Da / Num. of mol.: 21 / Source method: obtained synthetically / Formula: PO4
#8: Chemical ChemComp-7E4 / 11-[(2~{S})-2-[(2-pyridin-3-ylquinazolin-4-yl)amino]-2,3-dihydro-1~{H}-inden-5-yl]undec-10-ynoic acid


Mass: 518.649 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C33H34N4O2
#9: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 681 / 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: 2.88 Å3/Da / Density % sol: 57.34 %
Crystal growTemperature: 293 K / Method: vapor diffusion / pH: 4.5
Details: 20 %w/v PEG 3350 0.2 M (NH4)2SO4 0.1 M Na Acet pH=4.50 0.50 %w/v LDAO

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06SA / Wavelength: 0.999 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Sep 16, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.999 Å / Relative weight: 1
ReflectionResolution: 2.2→102.65 Å / Num. obs: 125199 / % possible obs: 97.5 % / Observed criterion σ(I): 0 / Redundancy: 2.2 % / Rmerge(I) obs: 0.061
Reflection shellResolution: 2.2→2.45 Å / Redundancy: 2.2 % / Rmerge(I) obs: 0.431 / % possible all: 98.3

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Processing

Software
NameVersionClassification
REFMAC5.8.0049refinement
XDSdata reduction
XSCALEdata scaling
PHASERphasing
RefinementMethod to determine structure: OTHER / Resolution: 2.2→102.65 Å / Cor.coef. Fo:Fc: 0.955 / Cor.coef. Fo:Fc free: 0.95 / SU B: 6.074 / SU ML: 0.146 / Cross valid method: THROUGHOUT / ESU R: 0.229 / ESU R Free: 0.172 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.21014 1529 1.2 %RANDOM
Rwork0.18881 ---
obs0.18907 123670 97.56 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 39.374 Å2
Baniso -1Baniso -2Baniso -3
1--0.39 Å2-0 Å20.41 Å2
2---1.5 Å2-0 Å2
3---1.78 Å2
Refinement stepCycle: LAST / Resolution: 2.2→102.65 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms15714 0 518 681 16913
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0080.01916598
X-RAY DIFFRACTIONr_bond_other_d0.0040.0215230
X-RAY DIFFRACTIONr_angle_refined_deg1.5451.98122709
X-RAY DIFFRACTIONr_angle_other_deg1.056334938
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.4751993
X-RAY DIFFRACTIONr_dihedral_angle_2_deg36.32823.208689
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.783152428
X-RAY DIFFRACTIONr_dihedral_angle_4_deg16.4721585
X-RAY DIFFRACTIONr_chiral_restr0.0710.22496
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.02118465
X-RAY DIFFRACTIONr_gen_planes_other0.0040.023920
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_it5.0595.0217969
X-RAY DIFFRACTIONr_mcbond_other5.0575.0217968
X-RAY DIFFRACTIONr_mcangle_it6.1728.4629963
X-RAY DIFFRACTIONr_mcangle_other6.1728.4629964
X-RAY DIFFRACTIONr_scbond_it6.3625.5358629
X-RAY DIFFRACTIONr_scbond_other6.1915.5028546
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other7.9269.08912621
X-RAY DIFFRACTIONr_long_range_B_refined8.68322.73518535
X-RAY DIFFRACTIONr_long_range_B_other8.61922.68318316
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
Refine LS restraints NCS

Refine-ID: X-RAY DIFFRACTION / Type: interatomic distance / Weight position: 0.05

Ens-IDDom-IDAuth asym-IDNumberRms dev position (Å)
11A311000.06
12B311000.06
21A309180.06
22C309180.06
31A314690.04
32D314690.04
41B311120.05
42C311120.05
51B312070.05
52D312070.05
61C308390.05
62D308390.05
LS refinement shellResolution: 2.2→2.257 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.352 125 -
Rwork0.296 9217 -
obs--98.52 %

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