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- PDB-7p2z: Crystal structure of human lysosomal acid-alpha-glucosidase, GAA,... -

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Basic information

Entry
Database: PDB / ID: 7p2z
TitleCrystal structure of human lysosomal acid-alpha-glucosidase, GAA, in complex with cyclosulfamidate 4
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 / alpha-1,4-glucosidase activity / sucrose metabolic process / Glycogen storage disease type II (GAA) / glycophagy / alpha-glucosidase / maltose alpha-glucosidase activity ...vacuolar sequestering / autolysosome lumen / maltose metabolic process / alpha-glucosidase activity / alpha-1,4-glucosidase activity / sucrose metabolic process / Glycogen storage disease type II (GAA) / glycophagy / alpha-glucosidase / maltose alpha-glucosidase activity / diaphragm contraction / neuromuscular process controlling posture / tissue development / regulation of the force of heart contraction / glycogen catabolic process / aorta development / azurophil granule membrane / Glycogen breakdown (glycogenolysis) / muscle cell cellular homeostasis / lysosome organization / tertiary granule membrane / neuromuscular process controlling balance / 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
TRIETHYLENE GLYCOL / Chem-YTW / Lysosomal alpha-glucosidase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 1.85 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

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
AAA: Lysosomal alpha-glucosidase
AaA: Lysosomal alpha-glucosidase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)198,27232
Polymers193,9572
Non-polymers4,31530
Water14,016778
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area9130 Å2
ΔGint-89 kcal/mol
Surface area31280 Å2
MethodPISA
Unit cell
Length a, b, c (Å)97.157, 102.539, 129.048
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, 2 molecules AAAAaA

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


Mass: 96978.633 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Details: sample source 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 , 4 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.: 2
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

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Non-polymers , 7 types, 803 molecules

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


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


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


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


Mass: 62.068 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: C2H6O2 / Feature type: SUBJECT OF INVESTIGATION
#10: Chemical ChemComp-YTW / (3~{a}~{R},4~{S},5~{S},6~{S},7~{R},7~{a}~{S})-7-(hydroxymethyl)-2,2-bis(oxidanylidene)-3~{a},4,5,6,7,7~{a}-hexahydro-3~{H}-benzo[d][1,2,3]oxathiazole-4,5,6-triol


Mass: 255.246 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C7H13NO7S / Feature type: SUBJECT OF INVESTIGATION
#11: Chemical ChemComp-PGE / TRIETHYLENE GLYCOL / Polyethylene glycol


Mass: 150.173 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C6H14O4 / Feature type: SUBJECT OF INVESTIGATION
#12: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 778 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestY

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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: 63 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 7
Details: 1.9 M AMMONIUM SULPHATE, 0.1 M HEPES REMARK 280 PH 7.0, 2% V/V PEG400

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SOLEIL / Beamline: PROXIMA 2 / Wavelength: 0.9801 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: 0.9801 Å / Relative weight: 1
ReflectionResolution: 1.85→47.65 Å / Num. obs: 110461 / % possible obs: 100 % / Redundancy: 13.6 % / Biso Wilson estimate: 20.85 Å2 / CC1/2: 0.998 / Rmerge(I) obs: 0.121 / Rpim(I) all: 0.049 / Rrim(I) all: 0.13 / Net I/σ(I): 14.5
Reflection shellResolution: 1.85→1.88 Å / Rmerge(I) obs: 1.554 / Mean I/σ(I) obs: 2.1 / Num. unique obs: 5401 / CC1/2: 0.742 / Rpim(I) all: 0.628 / % possible all: 99.9

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Processing

Software
NameVersionClassification
REFMAC5.8.0266refinement
XDSdata reduction
Aimlessdata scaling
REFMACphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS
Starting model: 5nn4

5nn4


Resolution: 1.85→47 Å / Cor.coef. Fo:Fc: 0.975 / Cor.coef. Fo:Fc free: 0.966 / SU B: 2.132 / SU ML: 0.062 / Cross valid method: FREE R-VALUE / ESU R: 0.091 / ESU R Free: 0.09
Details: Hydrogens have been added in their riding positions
RfactorNum. reflection% reflectionSelection details
Rfree0.1753 5503 4.986 %taken over form entry 5NN4
Rwork0.1485 104870 --
all0.15 ---
obs0.14978 110373 99.952 %-
Solvent computationIon probe radii: 0.7 Å / Shrinkage radii: 0.7 Å / VDW probe radii: 1.1 Å / Solvent model: MASK BULK SOLVENT
Displacement parametersBiso mean: 28.703 Å2
Baniso -1Baniso -2Baniso -3
1-1.237 Å2-0 Å20 Å2
2---0.8 Å2-0 Å2
3----0.437 Å2
Refinement stepCycle: LAST / Resolution: 1.85→47 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6691 0 265 778 7734
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0090.0137217
X-RAY DIFFRACTIONr_bond_other_d0.0010.0176554
X-RAY DIFFRACTIONr_angle_refined_deg1.5131.6839884
X-RAY DIFFRACTIONr_angle_other_deg1.3551.59715147
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.8465866
X-RAY DIFFRACTIONr_dihedral_angle_2_deg32.27422.173359
X-RAY DIFFRACTIONr_dihedral_angle_3_deg11.954151052
X-RAY DIFFRACTIONr_dihedral_angle_4_deg15.7511541
X-RAY DIFFRACTIONr_chiral_restr0.0770.2949
X-RAY DIFFRACTIONr_gen_planes_refined0.0080.028105
X-RAY DIFFRACTIONr_gen_planes_other0.0010.021664
X-RAY DIFFRACTIONr_nbd_refined0.1940.21240
X-RAY DIFFRACTIONr_symmetry_nbd_other0.1840.26001
X-RAY DIFFRACTIONr_nbtor_refined0.170.23447
X-RAY DIFFRACTIONr_symmetry_nbtor_other0.0820.23116
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1790.2571
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_other0.0920.23
X-RAY DIFFRACTIONr_symmetry_nbd_refined0.1470.211
X-RAY DIFFRACTIONr_nbd_other0.2420.244
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_refined0.1610.220
X-RAY DIFFRACTIONr_mcbond_it4.6422.5713429
X-RAY DIFFRACTIONr_mcbond_other4.6412.573428
X-RAY DIFFRACTIONr_mcangle_it4.973.8174288
X-RAY DIFFRACTIONr_mcangle_other4.9693.8184289
X-RAY DIFFRACTIONr_scbond_it12.1113.2743788
X-RAY DIFFRACTIONr_scbond_other12.113.2763789
X-RAY DIFFRACTIONr_scangle_it11.8574.6155589
X-RAY DIFFRACTIONr_scangle_other11.8564.6165590
X-RAY DIFFRACTIONr_lrange_it10.82932.2717976
X-RAY DIFFRACTIONr_lrange_other10.88231.67784
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.85-1.8980.3223950.3157706X-RAY DIFFRACTION99.8767
1.898-1.950.2913790.2827436X-RAY DIFFRACTION100
1.95-2.0060.2663930.2437286X-RAY DIFFRACTION99.987
2.006-2.0680.2293640.27093X-RAY DIFFRACTION100
2.068-2.1360.2033710.1636835X-RAY DIFFRACTION100
2.136-2.2110.1693500.1416649X-RAY DIFFRACTION99.9857
2.211-2.2940.23310.1426405X-RAY DIFFRACTION100
2.294-2.3880.183250.1366214X-RAY DIFFRACTION100
2.388-2.4940.1633180.1285935X-RAY DIFFRACTION100
2.494-2.6160.1712970.1285661X-RAY DIFFRACTION100
2.616-2.7570.172820.1335414X-RAY DIFFRACTION100
2.757-2.9240.1642690.1355128X-RAY DIFFRACTION100
2.924-3.1250.1842570.144832X-RAY DIFFRACTION100
3.125-3.3750.1662330.1394506X-RAY DIFFRACTION100
3.375-3.6970.152200.1354167X-RAY DIFFRACTION100
3.697-4.1320.1362010.1173796X-RAY DIFFRACTION100
4.132-4.7690.1261760.1093357X-RAY DIFFRACTION100
4.769-5.8360.1711540.1422866X-RAY DIFFRACTION100
5.836-8.2320.1981190.1842260X-RAY DIFFRACTION100
8.232-470.17690.1881324X-RAY DIFFRACTION99.2165

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