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- PDB-2nsx: Structure of acid-beta-glucosidase with pharmacological chaperone... -

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Basic information

Entry
Database: PDB / ID: 2nsx
TitleStructure of acid-beta-glucosidase with pharmacological chaperone provides insight into Gaucher disease
ComponentsGlucosylceramidase
KeywordsHYDROLASE / TIM-barrel glycosidase Cerezyme hydrolysis
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 / galactosylceramidase / termination of signal transduction / galactosylceramidase activity / positive regulation of autophagy of mitochondrion in response to mitochondrial depolarization / 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 / galactosylceramidase / termination of signal transduction / galactosylceramidase activity / positive regulation of autophagy of mitochondrion in response to mitochondrial depolarization / lymphocyte migration / glucosylceramidase / glucosylceramide catabolic process / scavenger receptor binding / regulation of lysosomal protein catabolic process / sphingosine biosynthetic process / autophagosome organization / glucosylceramidase activity / microglial cell proliferation / regulation of TOR signaling / glucosyltransferase activity / ceramide biosynthetic process / lipid storage / response to thyroid hormone / 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 testosterone / response to dexamethasone / Association of TriC/CCT with target proteins during biosynthesis / negative regulation of interleukin-6 production / homeostasis of number of cells / antigen processing and presentation / regulation of macroautophagy / establishment of skin barrier / negative regulation of protein-containing complex assembly / positive regulation of protein dephosphorylation / cell maturation / cholesterol metabolic process / respiratory electron transport chain / cellular response to starvation / lysosomal lumen / negative regulation of MAP kinase activity / 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 / T cell differentiation in thymus / cellular response to tumor necrosis factor / 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
5-HYDROXYMETHYL-3,4-DIHYDROXYPIPERIDINE / Lysosomal acid glucosylceramidase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.11 Å
AuthorsLieberman, R.L. / Petsko, G.A. / Ringe, D.
CitationJournal: Nat.Chem.Biol. / Year: 2007
Title: Structure of acid beta-glucosidase with pharmacological chaperone provides insight into Gaucher disease.
Authors: Lieberman, R.L. / Wustman, B.A. / Huertas, P. / Powe, A.C. / Pine, C.W. / Khanna, R. / Schlossmacher, M.G. / Ringe, D. / Petsko, G.A.
History
DepositionNov 6, 2006Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 26, 2006Provider: repository / Type: Initial release
Revision 1.1May 1, 2008Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Non-polymer description / Version format compliance
Revision 1.3Oct 18, 2017Group: Refinement description / Category: software / Item: _software.name
Revision 2.0Jul 29, 2020Group: Advisory / Atomic model ...Advisory / Atomic model / Data collection / Database references / Derived calculations / Non-polymer description / Structure summary
Category: atom_site / chem_comp ...atom_site / chem_comp / database_PDB_caveat / entity / pdbx_chem_comp_identifier / pdbx_entity_nonpoly / pdbx_nonpoly_scheme / pdbx_validate_chiral / struct_asym / struct_conn / struct_ref_seq_dif / 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_atom_id / _atom_site.auth_comp_id / _atom_site.label_atom_id / _atom_site.label_comp_id / _atom_site.label_entity_id / _atom_site.type_symbol / _chem_comp.formula / _chem_comp.formula_weight / _chem_comp.id / _chem_comp.mon_nstd_flag / _chem_comp.name / _chem_comp.pdbx_synonyms / _chem_comp.type / _pdbx_nonpoly_scheme.entity_id / _pdbx_nonpoly_scheme.mon_id / _pdbx_nonpoly_scheme.pdb_mon_id / _struct_asym.entity_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_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr2_auth_asym_id / _struct_conn.ptnr2_auth_comp_id / _struct_conn.ptnr2_label_asym_id / _struct_conn.ptnr2_label_comp_id / _struct_ref_seq_dif.details
Description: Carbohydrate remediation / Provider: repository / Type: Remediation
Revision 2.1Aug 30, 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

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)225,87431
Polymers222,5614
Non-polymers3,31427
Water18,1231006
1
A: Glucosylceramidase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)56,4348
Polymers55,6401
Non-polymers7947
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Glucosylceramidase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)56,80610
Polymers55,6401
Non-polymers1,1669
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
3
C: Glucosylceramidase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)56,2426
Polymers55,6401
Non-polymers6015
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
4
D: Glucosylceramidase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)56,3937
Polymers55,6401
Non-polymers7536
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
5
A: Glucosylceramidase
B: Glucosylceramidase
hetero molecules

C: Glucosylceramidase
D: Glucosylceramidase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)225,87431
Polymers222,5614
Non-polymers3,31427
Water724
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation1_565x,y+1,z1
Buried area10490 Å2
ΔGint-250 kcal/mol
Surface area69910 Å2
MethodPISA
6


  • Idetical with deposited unit
  • defined by software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area12710 Å2
ΔGint-249 kcal/mol
Surface area67690 Å2
MethodPISA
7
A: Glucosylceramidase
B: Glucosylceramidase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)113,24018
Polymers111,2802
Non-polymers1,96016
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4400 Å2
ΔGint-127 kcal/mol
Surface area35870 Å2
MethodPISA
8
C: Glucosylceramidase
D: Glucosylceramidase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)112,63413
Polymers111,2802
Non-polymers1,35411
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4120 Å2
ΔGint-107 kcal/mol
Surface area36010 Å2
MethodPISA
9
A: Glucosylceramidase
hetero molecules

C: Glucosylceramidase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)112,67514
Polymers111,2802
Non-polymers1,39512
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation1_565x,y+1,z1
Buried area3720 Å2
ΔGint-100 kcal/mol
Surface area36160 Å2
MethodPISA
Unit cell
Length a, b, c (Å)108.967, 92.216, 152.670
Angle α, β, γ (deg.)90.00, 110.94, 90.00
Int Tables number4
Space group name H-MP1211

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Components

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Protein / Sugars , 2 types, 9 molecules ABCD

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


Mass: 55640.168 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GBA / 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.: 5
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, 1028 molecules

#3: Chemical
ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 18 / Source method: obtained synthetically / Formula: SO4
#4: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL / Glycerol


Mass: 92.094 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C3H8O3
#5: Chemical ChemComp-IFM / 5-HYDROXYMETHYL-3,4-DIHYDROXYPIPERIDINE / Afegostat / isofagomine / (3R,4R,5R)-5-(HYDROXYMETHYL)PIPERIDINE-3,4-DIOL / Afegostat


Mass: 147.172 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C6H13NO3
#6: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 1006 / 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: 3.22 Å3/Da / Density % sol: 61.76 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 4.5
Details: 1 M Ammonium Sulfate 0.17 M Guanidinium HCl 0.02 M KCl 0.1 M Acetate buffer pH 4.5, VAPOR DIFFUSION, HANGING DROP, temperature 298K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 23-ID-B / Wavelength: 1 Å
DetectorType: MARRESEARCH / Detector: CCD / Date: Sep 30, 2005
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.1→50 Å / Num. all: 149310 / Num. obs: 149310 / % possible obs: 91.5 % / Redundancy: 3.8 % / Biso Wilson estimate: 36 Å2 / Rsym value: 0.078 / Net I/σ(I): 13.1
Reflection shellResolution: 2.1→2.16 Å / Redundancy: 3.3 % / Mean I/σ(I) obs: 3 / Num. unique all: 11457 / Rsym value: 0.356 / % possible all: 70.4

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Processing

Software
NameVersionClassification
REFMAC5.2.0005refinement
MAR345345DTBdata collection
HKL-2000data reduction
HKL-2000data scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1OGS

1ogs


Resolution: 2.11→50 Å / Cor.coef. Fo:Fc: 0.956 / Cor.coef. Fo:Fc free: 0.936 / SU B: 4.902 / SU ML: 0.128 / Cross valid method: THROUGHOUT / ESU R: 0.201 / ESU R Free: 0.179 / Stereochemistry target values: MAXIMUM LIKELIHOOD
RfactorNum. reflection% reflectionSelection details
Rfree0.23492 7504 5 %RANDOM
Rwork0.191 ---
obs0.19319 141806 91.27 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 36.102 Å2
Baniso -1Baniso -2Baniso -3
1-4.93 Å20 Å2-0.71 Å2
2---3 Å20 Å2
3----2.44 Å2
Refinement stepCycle: LAST / Resolution: 2.11→50 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms15720 0 192 1006 16918
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0140.02216449
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.5271.95622485
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.87851984
X-RAY DIFFRACTIONr_dihedral_angle_2_deg37.2123.444720
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.335152516
X-RAY DIFFRACTIONr_dihedral_angle_4_deg21.7391584
X-RAY DIFFRACTIONr_chiral_restr0.1060.22422
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.0212536
X-RAY DIFFRACTIONr_gen_planes_other
X-RAY DIFFRACTIONr_nbd_refined0.2210.28228
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined0.310.211015
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.170.21161
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.1840.273
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.110.220
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it0.8871.510178
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it1.45216072
X-RAY DIFFRACTIONr_scbond_it2.08937136
X-RAY DIFFRACTIONr_scangle_it3.1754.56287
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.105→2.16 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.325 422 -
Rwork0.246 7613 -
obs--66.51 %

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