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- PDB-3rik: The acid beta-glucosidase active site exhibits plasticity in bind... -

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Basic information

Entry
Database: PDB / ID: 3rik
TitleThe acid beta-glucosidase active site exhibits plasticity in binding 3,4,5,6-tetrahydroxyazepane-based inhibitors: implications for pharmacological chaperone design for gaucher disease
ComponentsGlucosylceramidase
KeywordsHYDROLASE/HYDROLASE INHIBITOR / TIM-Barrel / Lysosomal Hydrolase / Hydrolase / Glycosylation / Lysosome / HYDROLASE-HYDROLASE INHIBITOR complex
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 / 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 / Transferases; Glycosyltransferases; Hexosyltransferases / neuromuscular process / hematopoietic stem cell proliferation / lysosome organization / response to dexamethasone / response to testosterone / Association of TriC/CCT with target proteins during biosynthesis / 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 / cellular response to starvation / lysosomal lumen / 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 / 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-3RI / Lysosomal acid glucosylceramidase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / RIGID BODY REFINEMENT / Resolution: 2.48 Å
AuthorsOrwig, S.D. / Lieberman, R.L.
CitationJournal: Biochemistry / Year: 2011
Title: Binding of 3,4,5,6-tetrahydroxyazepanes to the acid-beta-glucosidase active site: implications for pharmacological chaperone design for Gaucher disease
Authors: Orwig, S.D. / Tan, Y.L. / Grimster, N.P. / Yu, Z. / Powers, E.T. / Kelly, J.W. / Lieberman, R.L.
History
DepositionApr 13, 2011Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 14, 2012Provider: repository / Type: Initial release
Revision 1.1Dec 5, 2012Group: Derived calculations
Revision 1.2Aug 15, 2018Group: Advisory / Data collection / Derived calculations
Category: pdbx_distant_solvent_atoms / pdbx_struct_assembly ...pdbx_distant_solvent_atoms / pdbx_struct_assembly / pdbx_struct_assembly_gen / pdbx_struct_assembly_prop
Revision 1.3Jul 29, 2020Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Structure summary
Category: chem_comp / entity ...chem_comp / entity / pdbx_chem_comp_identifier / pdbx_entity_nonpoly / struct_conn / struct_ref_seq_dif / 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 / _struct_conn.pdbx_dist_value / _struct_conn.pdbx_leaving_atom_flag / _struct_conn.pdbx_role / _struct_conn.ptnr1_auth_asym_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 / _struct_ref_seq_dif.details
Description: Carbohydrate remediation / Provider: repository / Type: Remediation
Revision 1.4Oct 9, 2024Group: Data collection / Database references / Structure summary
Category: chem_comp / chem_comp_atom ...chem_comp / chem_comp_atom / chem_comp_bond / database_2 / pdbx_entry_details / pdbx_modification_feature
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
C: Glucosylceramidase
D: Glucosylceramidase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)227,12644
Polymers222,5614
Non-polymers4,56540
Water16,358908
1
A: Glucosylceramidase
B: Glucosylceramidase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)113,65923
Polymers111,2802
Non-polymers2,37921
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4650 Å2
ΔGint-192 kcal/mol
Surface area36290 Å2
MethodPISA
2
C: Glucosylceramidase
D: Glucosylceramidase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)113,46721
Polymers111,2802
Non-polymers2,18719
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4650 Å2
ΔGint-202 kcal/mol
Surface area36440 Å2
MethodPISA
Unit cell
Length a, b, c (Å)107.980, 91.553, 152.213
Angle α, β, γ (deg.)90.00, 110.70, 90.00
Int Tables number4
Space group name H-MP1211

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Components

#1: Protein
Glucosylceramidase / Acid beta-glucosidase / Alglucerase / Beta-glucocerebrosidase / D-glucosyl-N-acylsphingosine ...Acid beta-glucosidase / Alglucerase / Beta-glucocerebrosidase / D-glucosyl-N-acylsphingosine glucohydrolase / Imiglucerase


Mass: 55640.168 Da / Num. of mol.: 4 / Fragment: Residues 40-536
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GBA, GC, GLUC / Production host: Cricetulus griseus (Chinese hamster) / References: UniProt: P04062, glucosylceramidase
#2: Chemical...
ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 34 / Source method: obtained synthetically / Formula: SO4
#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.: 4
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
#4: Chemical ChemComp-3RI / (3S,4R,5R,6S)-1-(2-hydroxyethyl)azepane-3,4,5,6-tetrol


Mass: 207.224 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C8H17NO5
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 908 / Source method: isolated from a natural source / Formula: H2O
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: 3.16 Å3/Da / Density % sol: 61.1 %
Crystal growTemperature: 298 K / pH: 4.6
Details: 11-12% PEG 3350, 0.18-0.205 M ammonium sulfate, and 0.1 M acetate buffer, pH 4.6, VAPOR DIFFUSION, HANGING DROP, temperature 298.0K

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Data collection

Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 22-BM / Wavelength: 1
DetectorType: MARMOSAIC 225 mm CCD / Detector: CCD / Date: Nov 1, 2007
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.48→46.5 Å / Num. obs: 88126 / Redundancy: 2.9 % / Rsym value: 0.122

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Processing

Software
NameClassification
SERGUIdata collection
REFMACrefinement
HKL-2000data reduction
HKL-2000data scaling
REFMACphasing
RefinementMethod to determine structure: RIGID BODY REFINEMENT / Resolution: 2.48→46.5 Å / Cor.coef. Fo:Fc: 0.955 / Cor.coef. Fo:Fc free: 0.915 / SU B: 7.662 / SU ML: 0.168 / Cross valid method: THROUGHOUT / ESU R: 0.377 / ESU R Free: 0.254 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN USED IF PRESENT IN THE INPUT
RfactorNum. reflection% reflectionSelection details
Rfree0.225 4628 5 %RANDOM
Rwork0.162 ---
obs0.165 88126 94.3 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 27.99 Å2
Baniso -1Baniso -2Baniso -3
1-0 Å20 Å2-0.01 Å2
2--0 Å20 Å2
3----0.01 Å2
Refinement stepCycle: LAST / Resolution: 2.48→46.5 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms15716 0 254 908 16878
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0160.0216428
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.7941.95922426
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.02251984
X-RAY DIFFRACTIONr_dihedral_angle_2_deg38.04523.444720
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.292152516
X-RAY DIFFRACTIONr_dihedral_angle_4_deg20.7441584
X-RAY DIFFRACTIONr_chiral_restr0.1130.22456
X-RAY DIFFRACTIONr_gen_planes_refined0.0090.02112520
X-RAY DIFFRACTIONr_gen_planes_other
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_it0.221.59936
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it0.411216064
X-RAY DIFFRACTIONr_scbond_it0.39736492
X-RAY DIFFRACTIONr_scangle_it0.7074.56362
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.48→2.55 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.343 267 -
Rwork0.233 4899 -
obs--71.99 %

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