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- PDB-8k7h: Crystal structure of human lysosomal alpha-galactosidase A in com... -

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Basic information

Entry
Database: PDB / ID: 8k7h
TitleCrystal structure of human lysosomal alpha-galactosidase A in complex with (2R,3S,4R)-2-(hydroxymethyl)-1-methylpyrrolidine-3,4-diol
ComponentsAlpha-galactosidase A
KeywordsHYDROLASE / alpha-galactosidase / glycosidase / iminosugar
Function / homology
Function and homology information


glycosylceramide catabolic process / negative regulation of nitric-oxide synthase activity / alpha-galactosidase / alpha-galactosidase activity / glycosphingolipid catabolic process / oligosaccharide metabolic process / glycoside catabolic process / galactoside binding / negative regulation of nitric oxide biosynthetic process / Glycosphingolipid catabolism ...glycosylceramide catabolic process / negative regulation of nitric-oxide synthase activity / alpha-galactosidase / alpha-galactosidase activity / glycosphingolipid catabolic process / oligosaccharide metabolic process / glycoside catabolic process / galactoside binding / negative regulation of nitric oxide biosynthetic process / Glycosphingolipid catabolism / catalytic activity / lysosomal lumen / azurophil granule lumen / lysosome / hydrolase activity / signaling receptor binding / Neutrophil degranulation / Golgi apparatus / protein homodimerization activity / extracellular exosome / extracellular region / cytoplasm
Similarity search - Function
Alpha galactosidase A, C-terminal beta-sandwich domain / Alpha galactosidase A C-terminal beta sandwich domain / Alpha galactosidase A / Glycoside hydrolase, family 27 / Glycoside hydrolase family 27/36, conserved site / Alpha-galactosidase signature. / Glycosyl hydrolase, all-beta / Aldolase-type TIM barrel / Glycoside hydrolase superfamily
Similarity search - Domain/homology
: / Alpha-galactosidase A
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.28 Å
AuthorsLi, H.Y. / Huang, K.F. / Ko, T.P. / Cheng, W.C.
Funding support Taiwan, 2items
OrganizationGrant numberCountry
Ministry of Science and Technology (MoST, Taiwan) Taiwan
Academia Sinica (Taiwan) Taiwan
CitationJournal: Jacs Au / Year: 2024
Title: Mechanistic Insights into Dibasic Iminosugars as pH-Selective Pharmacological Chaperones to Stabilize Human alpha-Galactosidase.
Authors: Li, H.Y. / Lin, H.Y. / Chang, S.K. / Chiu, Y.T. / Hou, C.C. / Ko, T.P. / Huang, K.F. / Niu, D.M. / Cheng, W.C.
History
DepositionJul 26, 2023Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Apr 10, 2024Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Alpha-galactosidase A
B: Alpha-galactosidase A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)93,53712
Polymers90,7892
Non-polymers2,74810
Water9,728540
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5310 Å2
ΔGint8 kcal/mol
Surface area30120 Å2
MethodPISA
Unit cell
Length a, b, c (Å)90.513, 90.513, 216.346
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number154
Space group name H-MP3221
Space group name HallP322"
Symmetry operation#1: x,y,z
#2: -y,x-y,z+2/3
#3: -x+y,-x,z+1/3
#4: x-y,-y,-z+1/3
#5: -x,-x+y,-z+2/3
#6: y,x,-z
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
d_1ens_1(chain "A" and (resid 32 through 692 or resid 716 through 800))
d_2ens_1(chain "B" and (resid 32 through 421 or resid 692 through 693 or resid 715 through 800))

NCS domain segments:

Ens-ID: ens_1

Dom-IDComponent-IDBeg auth comp-IDBeg label comp-IDEnd auth comp-IDEnd label comp-IDAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
d_11LEULEUMETMETAA32 - 4211 - 390
d_12NAGNAGNAGNAGAF501
d_13NAGNAGNAGNAGCC1
d_14NAGNAGNAGNAGDD2
d_15VMOVMOVMOVMOAG502
d_21LEULEUMETMETBB32 - 4211 - 390
d_22NAGNAGNAGNAGEE1
d_23NAGNAGNAGNAGEE2
d_24NAGNAGNAGNAGBJ502
d_25VMOVMOVMOVMOBK503

NCS oper: (Code: givenMatrix: (-0.975231035545, 0.217691585345, 0.0391765360797), (0.217050516547, 0.907755019923, 0.358984535979), (0.0425852154621, 0.35859614816, -0.932520939148)Vector: -88. ...NCS oper: (Code: given
Matrix: (-0.975231035545, 0.217691585345, 0.0391765360797), (0.217050516547, 0.907755019923, 0.358984535979), (0.0425852154621, 0.35859614816, -0.932520939148)
Vector: -88.4852529269, 19.0511779512, -48.8268641049)

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Components

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Protein , 1 types, 2 molecules AB

#1: Protein Alpha-galactosidase A / Alpha-D-galactosidase A / Alpha-D-galactoside galactohydrolase / ...Alpha-D-galactosidase A / Alpha-D-galactoside galactohydrolase / Galactosylgalactosylglucosylceramidase GLA / Melibiase


Mass: 45394.543 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GLA / Production host: Homo sapiens (human) / References: UniProt: P06280, alpha-galactosidase

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Sugars , 3 types, 6 molecules

#2: 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
#3: Polysaccharide alpha-D-mannopyranose-(1-3)-beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1- ...alpha-D-mannopyranose-(1-3)-beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 748.682 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DManpa1-3DManpb1-4DGlcpNAcb1-4DGlcpNAcb1-Glycam Condensed SequenceGMML 1.0
WURCS=2.0/3,4,3/[a2122h-1b_1-5_2*NCC/3=O][a1122h-1b_1-5][a1122h-1a_1-5]/1-1-2-3/a4-b1_b4-c1_c3-d1WURCSPDB2Glycan 1.1.0
[]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-Manp]{[(3+1)][a-D-Manp]{}}}}}LINUCSPDB-CARE
#4: 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.: 3 / Source method: obtained synthetically / 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 , 3 types, 544 molecules

#5: Chemical ChemComp-VMO / (2~{R},3~{S},4~{R})-2-(hydroxymethyl)-1-methyl-pyrrolidine-3,4-diol


Mass: 147.172 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C6H13NO3 / Feature type: SUBJECT OF INVESTIGATION
#6: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: SO4
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 540 / 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: 2.82 Å3/Da / Density % sol: 56.35 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 7.2
Details: 100 mM Tris-HCl buffer 7.2, 25% PEG4000 and 200 mM ammonium sulfate

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: NSRRC / Beamline: TPS 05A / Wavelength: 1 Å
DetectorType: RAYONIX MX300HE / Detector: CCD / Date: Mar 25, 2022
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.28→30 Å / Num. obs: 47648 / % possible obs: 100 % / Redundancy: 5.9 % / Biso Wilson estimate: 30.79 Å2 / Rmerge(I) obs: 0.159 / Net I/σ(I): 13.1
Reflection shellResolution: 2.28→2.36 Å / Rmerge(I) obs: 0.867 / Num. unique obs: 4650

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Processing

Software
NameVersionClassification
PHENIX1.19.2_4158refinement
HKL-2000data reduction
HKL-2000data scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1R47

1r47


Resolution: 2.28→29.63 Å / SU ML: 0.2573 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 21.8902
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2104 3751 4.43 %
Rwork0.171 81012 -
obs0.1727 45825 93.98 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 37.23 Å2
Refinement stepCycle: LAST / Resolution: 2.28→29.63 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6267 0 178 546 6991
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00326617
X-RAY DIFFRACTIONf_angle_d0.76068987
X-RAY DIFFRACTIONf_chiral_restr0.047962
X-RAY DIFFRACTIONf_plane_restr0.00741147
X-RAY DIFFRACTIONf_dihedral_angle_d15.18292412
Refine LS restraints NCSType: Torsion NCS / Rms dev position: 2.17418734545 Å
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.28-2.310.3068780.25711771X-RAY DIFFRACTION56.01
2.31-2.340.28211010.24251955X-RAY DIFFRACTION61.5
2.34-2.370.27541080.23142194X-RAY DIFFRACTION67.95
2.37-2.410.30361030.23482531X-RAY DIFFRACTION80.3
2.41-2.440.28241380.22932795X-RAY DIFFRACTION86.62
2.44-2.480.22951360.23562925X-RAY DIFFRACTION92.62
2.48-2.520.26171410.2343128X-RAY DIFFRACTION96.29
2.52-2.560.26641440.23333106X-RAY DIFFRACTION98.57
2.56-2.610.2651460.22523171X-RAY DIFFRACTION99.1
2.61-2.660.27051440.21413229X-RAY DIFFRACTION99.41
2.66-2.720.23991500.21233094X-RAY DIFFRACTION99.88
2.72-2.780.29841480.20643177X-RAY DIFFRACTION99.94
2.78-2.840.26361480.19773250X-RAY DIFFRACTION99.97
2.84-2.910.20111400.18943211X-RAY DIFFRACTION99.97
2.91-2.990.241460.18433159X-RAY DIFFRACTION100
2.99-3.080.2171460.18463217X-RAY DIFFRACTION99.97
3.08-3.180.24881480.17263154X-RAY DIFFRACTION100
3.18-3.290.2361420.16483204X-RAY DIFFRACTION100
3.29-3.420.16391440.15963181X-RAY DIFFRACTION99.94
3.42-3.580.21431540.13973220X-RAY DIFFRACTION100
3.58-3.760.15571530.14253211X-RAY DIFFRACTION100
3.77-40.17571480.13253144X-RAY DIFFRACTION100
4-4.310.1511500.12123230X-RAY DIFFRACTION99.97
4.31-4.740.15061480.12293185X-RAY DIFFRACTION100
4.74-5.420.1551490.14193187X-RAY DIFFRACTION100
5.42-6.820.23061460.17953204X-RAY DIFFRACTION100
6.83-29.630.22781520.18893179X-RAY DIFFRACTION99.58
Refinement TLS params.Method: refined / Origin x: -43.1078374935 Å / Origin y: 21.4739806166 Å / Origin z: -22.3569636398 Å
111213212223313233
T0.163537964268 Å20.00624331382186 Å20.0152297253579 Å2-0.134608608113 Å20.021308998202 Å2--0.177564727463 Å2
L0.413742997112 °20.0215627830105 °2-0.0915763011349 °2-0.311137147698 °2-0.109401706761 °2--0.559770957509 °2
S-0.0102750616385 Å °-0.0424263789494 Å °-0.0675928449361 Å °-0.00577607663164 Å °-0.047224182721 Å °-0.0171927988052 Å °-0.00553374379025 Å °0.0162844895382 Å °-0.0244253604795 Å °
Refinement TLS groupSelection details: all

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