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- PDB-7p32: Crystal structure of human lysosomal acid-alpha-glucosidase, GAA,... -

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Basic information

Entry
Database: PDB / ID: 7p32
TitleCrystal structure of human lysosomal acid-alpha-glucosidase, GAA, in complex with cyclosulfamidate 6
ComponentsLysosomal alpha-glucosidase
KeywordsHYDROLASE / alpha-glycosidase / lysosomal / Pompe disease / pharmacological chaperone
Function / homology
Function and homology information


vacuolar sequestering / autolysosome lumen / maltose metabolic process / alpha-glucosidase activity / sucrose metabolic process / Glycogen storage disease type II (GAA) / alpha-1,4-glucosidase activity / alpha-glucosidase / neuromuscular process controlling posture / glycophagy ...vacuolar sequestering / autolysosome lumen / maltose metabolic process / alpha-glucosidase activity / sucrose metabolic process / Glycogen storage disease type II (GAA) / alpha-1,4-glucosidase activity / alpha-glucosidase / neuromuscular process controlling posture / glycophagy / tissue development / diaphragm contraction / regulation of the force of heart contraction / glycogen catabolic process / aorta development / lysosome organization / azurophil granule membrane / neuromuscular process controlling balance / Glycogen breakdown (glycogenolysis) / muscle cell cellular homeostasis / tertiary granule membrane / ficolin-1-rich granule membrane / heart morphogenesis / cardiac muscle contraction / lysosomal lumen / locomotory behavior / glucose metabolic process / carbohydrate binding / lysosome / lysosomal membrane / intracellular membrane-bounded organelle / Neutrophil degranulation / extracellular exosome / membrane / plasma membrane
Similarity search - Function
P-type trefoil, conserved site / P-type 'Trefoil' domain signature. / Trefoil (P-type) domain / P-type trefoil domain / P-type trefoil domain superfamily / P-type 'Trefoil' domain profile. / P or trefoil or TFF domain / Glycosyl hydrolases family 31, conserved site / Glycosyl hydrolases family 31 signature 2. / Glycosyl hydrolases family 31, active site ...P-type trefoil, conserved site / P-type 'Trefoil' domain signature. / Trefoil (P-type) domain / P-type trefoil domain / P-type trefoil domain superfamily / P-type 'Trefoil' domain profile. / P or trefoil or TFF domain / Glycosyl hydrolases family 31, conserved site / Glycosyl hydrolases family 31 signature 2. / Glycosyl hydrolases family 31, active site / Glycosyl hydrolases family 31 active site. / Glycoside hydrolase family 31, N-terminal domain / Glycosyl hydrolase 31 N-terminal galactose mutarotase-like domain / : / Glycosyl hydrolase family 31 C-terminal domain / Glycoside hydrolase family 31 / Glycosyl hydrolases family 31 TIM-barrel domain / Galactose mutarotase-like domain superfamily / Glycosyl hydrolase, all-beta / Glycoside hydrolase superfamily
Similarity search - Domain/homology
Chem-56I / TRIETHYLENE GLYCOL / Lysosomal alpha-glucosidase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 1.82 Å
AuthorsRoig-Zamboni, V. / Kok, K. / Overkleeft, H. / Artola, M. / Sulzenbacher, G.
CitationJournal: J.Am.Chem.Soc. / Year: 2022
Title: 1,6- epi-Cyclophellitol Cyclosulfamidate Is a Bona Fide Lysosomal alpha-Glucosidase Stabilizer for the Treatment of Pompe Disease.
Authors: Kok, K. / Kuo, C.L. / Katzy, R.E. / Lelieveld, L.T. / Wu, L. / Roig-Zamboni, V. / van der Marel, G.A. / Codee, J.D.C. / Sulzenbacher, G. / Davies, G.J. / Overkleeft, H.S. / Aerts, J.M.F.G. / Artola, M.
History
DepositionJul 6, 2021Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jul 13, 2022Provider: repository / Type: Initial release
Revision 1.1Aug 31, 2022Group: 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.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Jan 31, 2024Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model
Revision 2.0Jul 31, 2024Group: Atomic model / Data collection ...Atomic model / Data collection / Source and taxonomy / Structure summary
Category: atom_site / chem_comp ...atom_site / chem_comp / entity_name_com / entity_src_gen / pdbx_nonpoly_scheme
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 / _chem_comp.type / _entity_name_com.name / _entity_src_gen.gene_src_common_name / _pdbx_nonpoly_scheme.auth_seq_num
Revision 2.1Nov 13, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature / Item: _pdbx_entry_details.has_protein_modification

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
AAA: Lysosomal alpha-glucosidase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)100,88029
Polymers96,9791
Non-polymers3,90128
Water12,250680
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area6160 Å2
ΔGint-76 kcal/mol
Surface area31210 Å2
MethodPISA
Unit cell
Length a, b, c (Å)97.043, 102.606, 129.118
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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Components

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Protein , 1 types, 1 molecules AAA

#1: Protein Lysosomal alpha-glucosidase / Acid maltase / Aglucosidase alfa / Myozyme


Mass: 96978.633 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Details: sample is Myozyme / Source: (gene. exp.) Homo sapiens (human) / Gene: GAA / Cell line (production host): OVARY CELLS / Production host: Cricetulus griseus (Chinese hamster) / References: UniProt: P10253, alpha-glucosidase

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Sugars , 5 types, 5 molecules

#2: Polysaccharide 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-[alpha-L-fucopyranose-(1-6)]2-acetamido-2-deoxy-beta- ...2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-[alpha-L-fucopyranose-(1-6)]2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 570.542 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DGlcpNAcb1-4[LFucpa1-6]DGlcpNAcb1-Glycam Condensed SequenceGMML 1.0
WURCS=2.0/2,3,2/[a2122h-1b_1-5_2*NCC/3=O][a1221m-1a_1-5]/1-1-2/a4-b1_a6-c1WURCSPDB2Glycan 1.1.0
[]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{}[(6+1)][a-L-Fucp]{}}}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 beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta- ...beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 586.542 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DManpb1-4DGlcpNAcb1-4DGlcpNAcb1-Glycam Condensed SequenceGMML 1.0
WURCS=2.0/2,3,2/[a2122h-1b_1-5_2*NCC/3=O][a1122h-1b_1-5]/1-1-2/a4-b1_b4-c1WURCSPDB2Glycan 1.1.0
[]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-Manp]{}}}}LINUCSPDB-CARE
#5: Polysaccharide alpha-L-fucopyranose-(1-6)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 367.349 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
LFucpa1-6DGlcpNAcb1-Glycam Condensed SequenceGMML 1.0
WURCS=2.0/2,2,1/[a2122h-1b_1-5_2*NCC/3=O][a1221m-1a_1-5]/1-2/a6-b1WURCSPDB2Glycan 1.1.0
[]{[(4+1)][b-D-GlcpNAc]{[(6+1)][a-L-Fucp]{}}}LINUCSPDB-CARE
#6: 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 / Feature type: SUBJECT OF INVESTIGATION
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 , 7 types, 703 molecules

#7: Chemical ChemComp-56I / [(1R,2R,3R,4R,5S)-2-(hydroxymethyl)-3,4,5-tris(oxidanyl)cyclohexyl]sulfamic acid


Mass: 257.261 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C7H15NO7S / Feature type: SUBJECT OF INVESTIGATION
#8: Chemical
ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: SO4 / Feature type: SUBJECT OF INVESTIGATION
#9: Chemical
ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 9 / Source method: obtained synthetically / Formula: Cl / Feature type: SUBJECT OF INVESTIGATION
#10: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C3H8O3 / Feature type: SUBJECT OF INVESTIGATION
#11: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C2H6O2 / Feature type: SUBJECT OF INVESTIGATION
#12: Chemical ChemComp-PGE / TRIETHYLENE GLYCOL


Mass: 150.173 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C6H14O4 / Feature type: SUBJECT OF INVESTIGATION
#13: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 680 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestY
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: 3.4 Å3/Da / Density % sol: 64 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 7
Details: 1.9 M AMMONIUM SULPHATE, 0.1 M HEPES PH 7.0, 2% V/V PEG400
PH range: 7

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SOLEIL / Beamline: PROXIMA 2 / Wavelength: 0.98009 Å
DetectorType: DECTRIS EIGER X 9M / Detector: PIXEL / Date: Sep 21, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.98009 Å / Relative weight: 1
ReflectionResolution: 1.82→47.68 Å / Num. obs: 115889 / % possible obs: 99.8 % / Redundancy: 13.5 % / Biso Wilson estimate: 23.36 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.1 / Rpim(I) all: 0.04 / Rrim(I) all: 0.108 / Net I/σ(I): 15.9
Reflection shellResolution: 1.82→1.85 Å / Redundancy: 11.7 % / Mean I/σ(I) obs: 1.5 / Num. unique obs: 5464 / CC1/2: 0.492 / Rpim(I) all: 0.705 / % possible all: 96.2

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Processing

Software
NameVersionClassification
REFMAC5.8.0267refinement
XDSdata reduction
Aimlessdata scaling
REFMACphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS
Starting model: 5NN4

5nn4


Resolution: 1.82→47 Å / Cor.coef. Fo:Fc: 0.975 / Cor.coef. Fo:Fc free: 0.966 / SU B: 2.063 / SU ML: 0.06 / Cross valid method: FREE R-VALUE / ESU R: 0.086 / ESU R Free: 0.086
Details: Hydrogens have been added in their riding positions
RfactorNum. reflection% reflectionSelection details
Rfree0.1754 5791 5.001 %taken over from 5NN4
Rwork0.15 110011 --
all0.151 ---
obs0.1513 115802 99.791 %-
Solvent computationIon probe radii: 0.7 Å / Shrinkage radii: 0.7 Å / VDW probe radii: 1 Å / Solvent model: MASK BULK SOLVENT
Displacement parametersBiso mean: 29.022 Å2
Baniso -1Baniso -2Baniso -3
1-0.589 Å2-0 Å20 Å2
2---0.326 Å2-0 Å2
3----0.263 Å2
Refinement stepCycle: LAST / Resolution: 1.82→47 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6668 0 237 680 7585
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0090.0137213
X-RAY DIFFRACTIONr_bond_other_d0.0020.0176560
X-RAY DIFFRACTIONr_angle_refined_deg1.5091.689888
X-RAY DIFFRACTIONr_angle_other_deg1.3661.59515164
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.7715875
X-RAY DIFFRACTIONr_dihedral_angle_2_deg32.28521.973365
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.189151065
X-RAY DIFFRACTIONr_dihedral_angle_4_deg17.5251544
X-RAY DIFFRACTIONr_chiral_restr0.0780.2947
X-RAY DIFFRACTIONr_gen_planes_refined0.0080.028093
X-RAY DIFFRACTIONr_gen_planes_other0.0010.021680
X-RAY DIFFRACTIONr_nbd_refined0.1960.21246
X-RAY DIFFRACTIONr_symmetry_nbd_other0.1850.26008
X-RAY DIFFRACTIONr_nbtor_refined0.170.23442
X-RAY DIFFRACTIONr_symmetry_nbtor_other0.0850.23107
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.170.2534
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_other0.030.21
X-RAY DIFFRACTIONr_symmetry_nbd_refined0.150.213
X-RAY DIFFRACTIONr_nbd_other0.2250.254
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_refined0.230.221
X-RAY DIFFRACTIONr_mcbond_it2.9982.7213427
X-RAY DIFFRACTIONr_mcbond_other2.9892.723426
X-RAY DIFFRACTIONr_mcangle_it3.5034.0544289
X-RAY DIFFRACTIONr_mcangle_other3.5034.0554290
X-RAY DIFFRACTIONr_scbond_it4.9233.2353786
X-RAY DIFFRACTIONr_scbond_other4.9233.2363787
X-RAY DIFFRACTIONr_scangle_it6.7874.6745585
X-RAY DIFFRACTIONr_scangle_other6.7874.6755586
X-RAY DIFFRACTIONr_lrange_it7.29533.2977960
X-RAY DIFFRACTIONr_lrange_other7.26432.6697779
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.819-1.8660.3554340.3297838X-RAY DIFFRACTION97.352
1.866-1.9170.244040.2627865X-RAY DIFFRACTION100
1.917-1.9730.2433960.2347666X-RAY DIFFRACTION100
1.973-2.0340.2173890.2017419X-RAY DIFFRACTION99.9744
2.034-2.10.2153790.1727210X-RAY DIFFRACTION99.9737
2.1-2.1740.1763680.1487005X-RAY DIFFRACTION99.9864
2.174-2.2560.1823580.1426724X-RAY DIFFRACTION100
2.256-2.3480.1883320.1396498X-RAY DIFFRACTION100
2.348-2.4520.1553360.136240X-RAY DIFFRACTION100
2.452-2.5720.1693100.1315982X-RAY DIFFRACTION100
2.572-2.7110.1693010.1345696X-RAY DIFFRACTION99.9833
2.711-2.8750.1792850.1415388X-RAY DIFFRACTION100
2.875-3.0730.1772640.1425086X-RAY DIFFRACTION100
3.073-3.3190.182520.1454717X-RAY DIFFRACTION100
3.319-3.6350.162340.144377X-RAY DIFFRACTION100
3.635-4.0630.1382050.1273992X-RAY DIFFRACTION100
4.063-4.690.1331870.1163527X-RAY DIFFRACTION100
4.69-5.7390.1661600.1353013X-RAY DIFFRACTION100
5.739-8.0960.1861240.1722385X-RAY DIFFRACTION100
8.096-470.183730.1891383X-RAY DIFFRACTION99.3179

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