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- PDB-6moz: Structure of acid-beta-glucosidase in complex with an aromatic py... -

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Basic information

Entry
Database: PDB / ID: 6moz
TitleStructure of acid-beta-glucosidase in complex with an aromatic pyrrolidine iminosugar inhibitor
ComponentsGlucosylceramidase
KeywordsHYDROLASE / TIM-BARREL / GLYCOSIDASE / CEREZYME / HYDROLYSIS / INHIBITOR COMPLEX / PHARMACOLOGICAL CHAPERONE
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 / 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-JXA / PHOSPHATE ION / Lysosomal acid glucosylceramidase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.1 Å
AuthorsPatterson-Orazem, A.C. / Lieberman, R.L.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Eye Institute (NIH/NEI)021205 United States
CitationJournal: Bioorg.Chem. / Year: 2019
Title: Exploring substituent diversity on pyrrolidine-aryltriazole iminosugars: Structural basis of beta-glucocerebrosidase inhibition.
Authors: Martinez-Bailen, M. / Carmona, A.T. / Patterson-Orazem, A.C. / Lieberman, R.L. / Ide, D. / Kubo, M. / Kato, A. / Robina, I. / Moreno-Vargas, A.J.
History
DepositionOct 5, 2018Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 19, 2019Provider: repository / Type: Initial release
Revision 1.1Dec 11, 2019Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.2Jul 29, 2020Group: Data collection / Derived calculations / Structure summary
Category: chem_comp / entity ...chem_comp / entity / pdbx_chem_comp_identifier / pdbx_entity_nonpoly / pdbx_struct_conn_angle / struct_conn / struct_conn_type / struct_site / struct_site_gen
Item: _chem_comp.name / _chem_comp.type ..._chem_comp.name / _chem_comp.type / _entity.pdbx_description / _pdbx_entity_nonpoly.name / _pdbx_struct_conn_angle.ptnr1_auth_asym_id / _pdbx_struct_conn_angle.ptnr1_auth_comp_id / _pdbx_struct_conn_angle.ptnr1_auth_seq_id / _pdbx_struct_conn_angle.ptnr1_label_asym_id / _pdbx_struct_conn_angle.ptnr1_label_atom_id / _pdbx_struct_conn_angle.ptnr1_label_comp_id / _pdbx_struct_conn_angle.ptnr1_label_seq_id / _pdbx_struct_conn_angle.ptnr2_auth_asym_id / _pdbx_struct_conn_angle.ptnr2_auth_seq_id / _pdbx_struct_conn_angle.ptnr2_label_asym_id / _pdbx_struct_conn_angle.ptnr2_symmetry / _pdbx_struct_conn_angle.ptnr3_auth_asym_id / _pdbx_struct_conn_angle.ptnr3_auth_comp_id / _pdbx_struct_conn_angle.ptnr3_auth_seq_id / _pdbx_struct_conn_angle.ptnr3_label_asym_id / _pdbx_struct_conn_angle.ptnr3_label_atom_id / _pdbx_struct_conn_angle.ptnr3_label_comp_id / _pdbx_struct_conn_angle.ptnr3_label_seq_id / _pdbx_struct_conn_angle.value / _struct_conn.conn_type_id / _struct_conn.id / _struct_conn.pdbx_dist_value / _struct_conn.pdbx_leaving_atom_flag / _struct_conn.pdbx_role / _struct_conn.ptnr1_auth_asym_id / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr1_symmetry / _struct_conn.ptnr2_auth_asym_id / _struct_conn.ptnr2_auth_comp_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id / _struct_conn.ptnr2_label_atom_id / _struct_conn.ptnr2_label_comp_id / _struct_conn.ptnr2_label_seq_id / _struct_conn.ptnr2_symmetry / _struct_conn_type.id
Description: Carbohydrate remediation / Provider: repository / Type: Remediation
Revision 1.3Oct 11, 2023Group: Data collection / Database references ...Data collection / Database references / Refinement description / Structure summary
Category: chem_comp / chem_comp_atom ...chem_comp / chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _chem_comp.pdbx_synonyms / _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Glucosylceramidase
B: Glucosylceramidase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)113,45044
Polymers111,2802
Non-polymers2,16942
Water2,018112
1
A: Glucosylceramidase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)56,82021
Polymers55,6401
Non-polymers1,18020
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Glucosylceramidase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)56,62923
Polymers55,6401
Non-polymers98922
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)110.280, 285.010, 91.680
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number20
Space group name H-MC2221
Components on special symmetry positions
IDModelComponents
11B-637-

HOH

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Components

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Protein / Sugars , 2 types, 4 molecules AB

#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: 55640.168 Da / Num. of mol.: 2 / Mutation: R514H
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GBA, GC, GLUC / Organ (production host): OVARY / Production host: Cricetulus griseus (Chinese hamster) / References: UniProt: P04062, glucosylceramidase
#2: 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.: 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 , 5 types, 152 molecules

#3: Chemical...
ChemComp-NA / SODIUM ION


Mass: 22.990 Da / Num. of mol.: 32 / Source method: obtained synthetically / Formula: Na
#4: Chemical ChemComp-JXA / (2R,3S,4R)-2-{[4-(3,5-dichlorophenyl)-1H-1,2,3-triazol-1-yl]methyl}pyrrolidine-3,4-diol


Mass: 329.182 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C13H14Cl2N4O2 / Feature type: SUBJECT OF INVESTIGATION
#5: Chemical
ChemComp-PO4 / PHOSPHATE ION / Phosphate


Mass: 94.971 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: PO4
#6: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL / Glycerol


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#7: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 112 / 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: 3.24 Å3/Da / Density % sol: 62 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 7
Details: HEPES pH 7.5, monobasic sodium phosphate and monobasic potassium phosphate
Temp details: room temperature

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Data collection

DiffractionMean temperature: 80 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 22-ID / Wavelength: 1 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Feb 21, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.1→45.8 Å / Num. obs: 84382 / % possible obs: 99.8 % / Redundancy: 13.8 % / CC1/2: 0.999 / Rmerge(I) obs: 0.1092 / Rpim(I) all: 0.0304 / Rrim(I) all: 0.1134 / Net I/σ(I): 15.4
Reflection shellResolution: 2.1→2.12 Å / Redundancy: 14.2 % / Rmerge(I) obs: 0.6151 / CC1/2: 0.97 / Rpim(I) all: 0.1689 / Rrim(I) all: 0.6381 / % possible all: 99.8

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Processing

Software
NameVersionClassification
PHENIX(1.11.1_2575)refinement
XDSdata reduction
XDSdata scaling
PHENIX(1.11.1_2575)phasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2NSX

2nsx


Resolution: 2.1→45.8 Å / SU ML: 0.25 / Cross valid method: THROUGHOUT / σ(F): 1.35 / Phase error: 31.19
RfactorNum. reflection% reflection
Rfree0.2278 3831 2.36 %
Rwork0.1998 --
obs0.2005 84382 99.77 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 2.1→45.8 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7851 0 117 112 8080
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0078222
X-RAY DIFFRACTIONf_angle_d0.86111230
X-RAY DIFFRACTIONf_dihedral_angle_d3.0966608
X-RAY DIFFRACTIONf_chiral_restr0.0531217
X-RAY DIFFRACTIONf_plane_restr0.0061439
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.1-2.12660.35061420.30595890X-RAY DIFFRACTION100
2.1266-2.15460.37371420.29035858X-RAY DIFFRACTION100
2.1546-2.18410.32181440.2735917X-RAY DIFFRACTION100
2.1841-2.21530.36641360.26945868X-RAY DIFFRACTION100
2.2153-2.24840.30861430.26395902X-RAY DIFFRACTION100
2.2484-2.28350.31391440.24645873X-RAY DIFFRACTION100
2.2835-2.32090.29121420.24185863X-RAY DIFFRACTION100
2.3209-2.3610.31381420.2385859X-RAY DIFFRACTION100
2.361-2.40390.25011400.23515902X-RAY DIFFRACTION100
2.4039-2.45010.24631450.21675885X-RAY DIFFRACTION100
2.4501-2.50010.24721420.22365819X-RAY DIFFRACTION100
2.5001-2.55450.29711430.22895860X-RAY DIFFRACTION99
2.5545-2.61390.28191400.23085858X-RAY DIFFRACTION99
2.6139-2.67930.29591450.22835850X-RAY DIFFRACTION100
2.6793-2.75170.27331390.21975910X-RAY DIFFRACTION100
2.7517-2.83270.25741370.2315840X-RAY DIFFRACTION100
2.8327-2.92410.24261430.21955940X-RAY DIFFRACTION100
2.9241-3.02860.24581390.22655885X-RAY DIFFRACTION100
3.0286-3.14980.26581370.22415877X-RAY DIFFRACTION100
3.1498-3.29310.24631390.21825903X-RAY DIFFRACTION100
3.2931-3.46670.20991440.20275873X-RAY DIFFRACTION100
3.4667-3.68380.22531380.17995897X-RAY DIFFRACTION100
3.6838-3.96810.19951490.16425878X-RAY DIFFRACTION100
3.9681-4.36720.15121410.15355901X-RAY DIFFRACTION100
4.3672-4.99850.1381440.14035859X-RAY DIFFRACTION100
4.9985-6.29530.21141460.17295895X-RAY DIFFRACTION100
6.2953-47.26410.19381450.1835881X-RAY DIFFRACTION100
Refinement TLS params.Method: refined / Origin x: 0.628 Å / Origin y: 325.2127 Å / Origin z: -1.2092 Å
111213212223313233
T0.2917 Å20.0193 Å20.0274 Å2-0.2513 Å20.0108 Å2--0.2368 Å2
L0.1799 °20.0856 °20.0612 °2-0.1988 °20.0299 °2--0.2245 °2
S-0.0023 Å °-0.0231 Å °-0.0048 Å °0.0537 Å °0.0049 Å °0.0257 Å °-0.1587 Å °-0.0087 Å °-0.0026 Å °
Refinement TLS groupSelection details: all

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