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- PDB-8k7e: Crystal structure of human lysosomal alpha-galactosidase A in com... -

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Basic information

Entry
Database: PDB / ID: 8k7e
TitleCrystal structure of human lysosomal alpha-galactosidase A in complex with (2R,3R,4S,5R)-2-(aminomethyl)-5-(hydroxymethyl)pyrrolidine-3,4-diol
ComponentsAlpha-galactosidase A
KeywordsHYDROLASE / alpha-galactosidase / glycosidase / iminosugar
Function / homology
Function and homology information


negative regulation of nitric-oxide synthase activity / glycosylceramide catabolic process / alpha-galactosidase / glycosphingolipid catabolic process / alpha-galactosidase activity / oligosaccharide metabolic process / glycoside catabolic process / negative regulation of nitric oxide biosynthetic process / Glycosphingolipid catabolism / catalytic activity ...negative regulation of nitric-oxide synthase activity / glycosylceramide catabolic process / alpha-galactosidase / glycosphingolipid catabolic process / alpha-galactosidase activity / oligosaccharide metabolic process / glycoside catabolic process / 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 / membrane / 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: 2.2 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
Revision 1.1Nov 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
A: Alpha-galactosidase A
B: Alpha-galactosidase A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)93,34511
Polymers90,7892
Non-polymers2,5569
Water9,908550
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4980 Å2
ΔGint1 kcal/mol
Surface area29860 Å2
MethodPISA
Unit cell
Length a, b, c (Å)90.370, 90.370, 216.423
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_15VLNVLNVLNVLNAG502
d_21LEULEUMETMETBB32 - 4211 - 390
d_22NAGNAGNAGNAGEE1
d_23NAGNAGNAGNAGEE2
d_24NAGNAGNAGNAGBI501
d_25VLNVLNVLNVLNBJ502

NCS oper: (Code: givenMatrix: (-0.974626087643, 0.220815261033, 0.0366689211687), (0.21884176115, 0.905571131266, 0.363385758932), (0.0470348047893, 0.362189931822, -0.930916849362)Vector: -88. ...NCS oper: (Code: given
Matrix: (-0.974626087643, 0.220815261033, 0.0366689211687), (0.21884176115, 0.905571131266, 0.363385758932), (0.0470348047893, 0.362189931822, -0.930916849362)
Vector: -88.5257451244, 19.3243884121, -48.658779447)

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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, 5 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.: 2 / 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, 554 molecules

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


Mass: 162.187 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C6H14N2O3 / 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.: 550 / 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: 2.81 Å3/Da / Density % sol: 56.23 %
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: 2.2→30 Å / Num. obs: 52803 / % possible obs: 100 % / Redundancy: 11 % / Biso Wilson estimate: 30.93 Å2 / Rmerge(I) obs: 0.134 / Net I/σ(I): 17.4
Reflection shellResolution: 2.2→2.28 Å / Rmerge(I) obs: 0.989 / Num. unique obs: 5184

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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: 2.2→29.58 Å / SU ML: 0.1983 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 20.9408
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.1923 3656 4.18 %
Rwork0.1596 83880 -
obs0.161 47850 87.44 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 39.19 Å2
Refinement stepCycle: LAST / Resolution: 2.2→29.58 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6261 0 166 557 6984
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00456599
X-RAY DIFFRACTIONf_angle_d0.88038962
X-RAY DIFFRACTIONf_chiral_restr0.0503956
X-RAY DIFFRACTIONf_plane_restr0.00661145
X-RAY DIFFRACTIONf_dihedral_angle_d14.73522406
Refine LS restraints NCSType: Torsion NCS / Rms dev position: 2.18880630221 Å
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.2-2.230.2126590.2091370X-RAY DIFFRACTION37.84
2.23-2.260.2407670.20211589X-RAY DIFFRACTION42.59
2.26-2.290.217870.21321710X-RAY DIFFRACTION47.46
2.29-2.330.2295880.2071925X-RAY DIFFRACTION51.85
2.33-2.360.23891000.19962174X-RAY DIFFRACTION59.16
2.36-2.40.28081070.1872550X-RAY DIFFRACTION69.46
2.4-2.440.24731360.1893125X-RAY DIFFRACTION82.33
2.44-2.490.21051380.19813230X-RAY DIFFRACTION90.34
2.49-2.540.24571560.20143490X-RAY DIFFRACTION94.33
2.54-2.590.26241610.19833653X-RAY DIFFRACTION98.78
2.59-2.640.22241620.19193715X-RAY DIFFRACTION99.95
2.64-2.710.25151570.18923637X-RAY DIFFRACTION99.95
2.71-2.770.23081660.18283698X-RAY DIFFRACTION100
2.77-2.850.27311600.18033701X-RAY DIFFRACTION99.97
2.85-2.930.24281660.1693707X-RAY DIFFRACTION99.97
2.93-3.030.20511560.17333677X-RAY DIFFRACTION99.97
3.03-3.130.20751520.16993713X-RAY DIFFRACTION100
3.13-3.260.19691600.16383697X-RAY DIFFRACTION100
3.26-3.410.17831560.15783659X-RAY DIFFRACTION100
3.41-3.590.19071600.14633698X-RAY DIFFRACTION100
3.59-3.810.18771510.13523712X-RAY DIFFRACTION100
3.81-4.10.14251720.1233698X-RAY DIFFRACTION100
4.11-4.520.14521700.11453690X-RAY DIFFRACTION100
4.52-5.170.14451620.12763657X-RAY DIFFRACTION99.97
5.17-6.50.18291510.16053722X-RAY DIFFRACTION100
6.5-29.580.17791560.18283683X-RAY DIFFRACTION99.84
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
10.798047821944-0.1114890311410.3320350355360.3414885436190.149864305090.2117650864840.0512455220885-0.09767404683590.1156793053930.02736571022650.039716736630.0624191896271-0.139201542656-0.09918914348450.0001768666247450.2560886640.06280073078610.01317698018890.2266886755690.01011523702860.234201491859-62.282307440932.7902040761-31.0502416594
20.175007056632-0.018905706743-0.05866503563290.1238413536570.1499830645250.1439076108430.0611577795920.0294277005745-0.00116338216398-0.0151673519403-0.05364177702980.179709540436-0.10139583414-0.3035615903668.20438351265E-50.2606210325540.03277230519960.00536650766170.3485075948410.0004475897215720.308260902215-76.707924987629.7474817021-32.5987337205
30.743479995678-0.0823231280909-0.5086158341670.3375393515010.4701953582070.8232436837610.03445518693210.224601308014-0.22056602337-0.0253701743825-0.1487138786780.1828623137790.0956873738627-0.27898714191-0.0007886601878340.2878287540030.00325329625083-0.03930427179420.272297901463-0.04893291249930.314594006126-66.686138618819.1809600011-43.0904449578
40.1264247621250.0533825229559-0.1040021381970.1048606300350.005077990953070.09968713476650.11854737125-0.0881361984943-0.237855342632-0.12558627111-0.02008826350390.03903812502490.169140096017-0.2693003321764.29974225616E-50.2968231116940.0358808906756-0.007821854106370.196927131561-0.004488011206450.235204825384-47.562293848717.2506168224-42.3533083956
50.854531093751-0.0928660756619-0.03842116811750.2782574006820.09998786153520.3404417730440.0341681332021-0.009807640705-0.025607774198-0.0878697114429-0.0363316037725-0.0200171684359-0.06315560809930.07812322241051.50245749801E-60.2478645289110.01140985244690.0174666685680.182110428040.01426356318730.187063587074-40.341610534527.8715119636-38.1214479976
60.1567427378510.0190900579721-0.02796472581050.151275475330.1777273531390.1061593009240.0125051192119-0.1867170685470.1637509659-0.2269464187580.126582547908-0.1049799472140.110406215530.2991353297859.03017676206E-50.323688830878-0.04354348115130.0621063168490.3015470878830.005613999999910.259764708209-28.577036276531.8656822721-41.7701685216
71.38889734960.786814686728-0.6492709447560.654230329653-0.3762234060081.10641872348-0.0992419838644-0.361811128758-0.167896507264-0.111331116846-0.241293901668-0.43933635404-0.02647389910010.50266503105-0.4463654777270.1894006134820.0466367208223-0.001897552744290.4060928011070.200079204560.411337668757-16.019454606717.4728890079-9.9551688739
80.424265052738-0.120651713482-0.2895255316210.39946929617-0.2908858409210.668806291584-0.228680637396-0.685335528534-0.7587998041010.110085953851-0.312041280466-0.4202076269660.5451100432940.504367926524-0.8849649450160.4825861107840.1574384873780.03496107823110.4656748205610.3304095852510.671103104003-22.43875458462.45704837122-2.27833236629
90.6765333544330.0998268399075-0.3895906313660.178591579403-0.0214019891490.519411470444-0.0675469340581-0.101600137903-0.2045578452180.0111990178608-0.11847009988-0.04919274763480.1733139122240.0456481370711-0.1298573390920.2976864828730.01971606448-0.0003008256007260.2187488566940.07042581726560.250204429382-36.836990139112.8712130665-7.32324479067
100.165356378166-0.00417459489575-0.01057058930850.0379408297205-0.01633727755260.02958193625170.118491798476-0.09409885263920.1325621802180.176859928788-0.06050370015450.0101481151936-0.1378851780050.0537075421153-3.31699782064E-50.286989384591-0.0203614340005-0.01567337603810.2307718052140.04172764742990.245791747549-33.684869824327.4939005166-7.97866831922
110.6048554009640.186203718894-0.2665978736930.63737517758-0.1669283316130.3599266318890.0376882122539-0.1150702583360.006860307920980.2636184132610.03727527676120.217954008743-0.122700796852-0.299557123237-0.006714380146510.292738471480.02331484171160.04973745630770.2550849758640.03818520910080.181759430747-52.901644820522.03474473410.0428836622807
Refinement TLS group

Refine-ID: X-RAY DIFFRACTION

IDRefine TLS-IDSelection detailsAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
11chain 'A' and (resid 32 through 90 )AA32 - 901 - 59
22chain 'A' and (resid 91 through 126 )AA91 - 12660 - 95
33chain 'A' and (resid 127 through 235 )AA127 - 23596 - 204
44chain 'A' and (resid 236 through 264 )AA236 - 264205 - 233
55chain 'A' and (resid 265 through 388 )AA265 - 388234 - 357
66chain 'A' and (resid 389 through 421 )AA389 - 421358 - 390
77chain 'B' and (resid 32 through 176 )BH32 - 1761 - 145
88chain 'B' and (resid 177 through 215 )BH177 - 215146 - 184
99chain 'B' and (resid 216 through 289 )BH216 - 289185 - 258
1010chain 'B' and (resid 290 through 320 )BH290 - 320259 - 289
1111chain 'B' and (resid 321 through 423 )BH321 - 423290 - 392

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