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- PDB-8k7i: Crystal structure of human lysosomal alpha-galactosidase A in com... -

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Basic information

Entry
Database: PDB / ID: 8k7i
TitleCrystal structure of human lysosomal alpha-galactosidase A in complex with (2R,3S,4R,5R)-2-(hydroxymethyl)-5-((methylamino)methyl)pyrrolidine-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: 2.12 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)94,87718
Polymers90,7892
Non-polymers4,08816
Water13,043724
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area7700 Å2
ΔGint-41 kcal/mol
Surface area30170 Å2
MethodPISA
Unit cell
Length a, b, c (Å)90.148, 90.148, 215.477
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
Components on special symmetry positions
IDModelComponents
11A-893-

HOH

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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 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.: 2
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
#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: 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 , 5 types, 734 molecules

#5: Chemical ChemComp-VN0 / (2~{R},3~{S},4~{R},5~{R})-2-(hydroxymethyl)-5-(methylaminomethyl)pyrrolidine-3,4-diol


Mass: 176.214 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C7H16N2O3 / Feature type: SUBJECT OF INVESTIGATION
#6: Chemical
ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: SO4
#7: Chemical ChemComp-P6G / HEXAETHYLENE GLYCOL / POLYETHYLENE GLYCOL PEG400


Mass: 282.331 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C12H26O7 / Comment: precipitant*YM
#8: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C3H8O3
#9: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 724 / 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: 2.78 Å3/Da / Density % sol: 55.76 %
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: 2.12→30 Å / Num. obs: 57776 / % possible obs: 99 % / Redundancy: 10.3 % / Biso Wilson estimate: 26.35 Å2 / Rmerge(I) obs: 0.118 / Net I/σ(I): 18.2
Reflection shellResolution: 2.12→2.2 Å / Rmerge(I) obs: 0.561 / Num. unique obs: 5223

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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: 2.12→29.51 Å / SU ML: 0.1806 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 19.1233
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.1945 1989 3.66 %
Rwork0.16 52324 -
obs0.1613 54313 93.13 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 33.19 Å2
Refinement stepCycle: LAST / Resolution: 2.12→29.51 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6261 0 267 728 7256
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00456717
X-RAY DIFFRACTIONf_angle_d0.79969112
X-RAY DIFFRACTIONf_chiral_restr0.047977
X-RAY DIFFRACTIONf_plane_restr0.00651151
X-RAY DIFFRACTIONf_dihedral_angle_d15.03852457
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.12-2.170.2735740.21481947X-RAY DIFFRACTION49.1
2.17-2.230.2298910.19762617X-RAY DIFFRACTION66.02
2.23-2.30.2371360.19453483X-RAY DIFFRACTION88.25
2.3-2.370.23541540.18673966X-RAY DIFFRACTION99.32
2.37-2.460.21271490.16753932X-RAY DIFFRACTION99.95
2.46-2.560.22811520.16343961X-RAY DIFFRACTION100
2.56-2.670.19791490.1553981X-RAY DIFFRACTION99.95
2.67-2.810.19931510.16024005X-RAY DIFFRACTION100
2.81-2.990.20351500.14843986X-RAY DIFFRACTION99.98
2.99-3.220.19871560.14674018X-RAY DIFFRACTION100
3.22-3.540.16371540.14024000X-RAY DIFFRACTION100
3.54-4.060.14921550.1354054X-RAY DIFFRACTION100
4.06-5.10.15821530.13854091X-RAY DIFFRACTION99.98
5.11-29.510.23881650.20644283X-RAY DIFFRACTION99.96
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)
10.151093522625-0.0256699602444-0.04358763311980.04817913750530.01501016069450.0232632186730.05815824231170.068022699866-0.1333555427390.0132627834748-0.05467255375910.08568096706890.1688908816-0.156911469365-0.002087126925330.194514333433-0.0561672229349-0.003437983719470.198480455133-0.02152355505650.19399304097528.5431314757-32.8725216101-5.12217451722
20.0548424862504-0.00589112088622-0.06003711312580.08871802001190.1284181981950.2277345636490.0801351533297-0.07248214525050.0604994815828-0.0307855883811-0.2085118905250.305212374921-0.0116414916832-0.477719927153-0.02990195664050.141536825238-0.03560396245610.02100305941450.325372254846-0.06784789021050.31052890987616.3636351109-25.92410788070.479854403302
30.0479095200736-0.01937222013860.04584709704860.020755411934-0.009807126696440.0561813568443-0.017941444441-0.149783082570.170436389650.1233096863-0.08751334222130.0726785712615-0.116374320348-0.213189076468-0.005425780053680.214626752971-0.02970821534680.04446782003020.239458397626-0.05465930526610.26002086401924.8972237346-16.797629349111.2792016858
40.2976432186170.01653141394460.09329593352660.1020650198750.09594666166050.2249923517710.0292211121176-0.0149889424464-0.00204277471390.0749343685308-0.04431025458-0.02394035973860.04474060789540.0149500354589-0.005559621318510.156062480572-0.0119857994346-0.008943939704590.1020479626010.01103033377290.12750843370346.9057071921-24.62199876893.50675545326
50.0136686978871-0.01207735503120.01270765665780.0167297407068-0.0006147166351260.008762795341650.0535247752602-0.0147929302626-0.1008832532490.0990511328070.0317577345396-0.06106519940850.1513554460760.1279129877840.01042194911880.2033564803430.0378546202555-0.06838611134120.1616472481810.02199970594860.17784477346562.273379899-31.23348509585.46342273366
64.793200801250.863879962884-3.570653815273.229495946131.096681223613.64513492836-0.3980529967970.538609132833-1.304759466680.346672809752-0.5813186287871.30470146660.382362164755-0.2047556865730.9768608318231.41280674995-0.04114801853920.001317235398661.316930721910.04411767134471.3509783393256.8886961652-39.647815604120.0505077988
70.163351748831-0.0522765918844-0.04417631827680.0462100425009-0.005210612669310.06924300616090.006462511949160.2209468810710.020556644733-0.0547888732373-0.186367550578-0.172859684480.1044868128140.484197929253-0.1728782498090.1365762054910.02315291107890.01884321863090.4381396112970.1192728935930.2556712936373.6954502751-20.6507249116-25.5017342923
80.0299570916920.01937292978880.01381442941890.007297734249410.001438607170770.0463326026829-0.06707766577260.1318308996640.104087424796-0.017417323443-0.126809809621-0.160905364135-0.09085603626570.226181283168-0.0943710114120.176051952504-0.30762515479-0.02354527640640.4768293744530.3249983996440.3855224811276.4676597907-6.14515529456-28.4565673326
90.0342530744414-0.0311473623237-0.02621901556220.0360440206385-0.02644235019280.0798296876354-0.1963805275240.1752104278610.135902043215-0.0488319874961-0.109951897879-0.119932242287-0.06380780570770.224532636992-0.2596635090420.237732494872-0.3165113596230.03401943455520.2752998384950.4662864921170.22825540248667.7575580088-2.01885336233-34.0733309759
100.104179542891-0.04497840417180.04780320051610.0525940670018-0.001416841564360.0324633018168-0.07114394234640.08728867460110.188829889245-0.0358632972547-0.0622691450003-0.00792119292856-0.09383620628230.130548000635-0.1189467357120.211667384223-0.00405077695736-0.01356822751180.1717242418230.07216816236520.18786181120453.3868176574-12.2047380287-28.6185547396
110.1213372977420.0958824132822-0.02215264720760.122987313702-0.001075419257770.1357922202640.006614152502020.1021144091870.0194655726388-0.0649417807075-0.0483758329573-0.00323525444582-0.00150698938514-0.027584188832-0.0772254953680.1793212114040.0353400089626-0.008990741301910.2017863042190.02810817879670.1332040107244.4326251515-21.3579306264-32.8666013962
120.007386663858710.003105458960290.001746988251090.0141520571870.01383900536750.008226961291270.05526652912680.0710349662966-0.078178301632-0.0757529610541-0.02891326202820.1219892635010.0718047040814-0.157484746033-0.003890934244860.247344994271-0.0136136371946-0.05104987734810.2868891533470.01633021549190.17574067555435.0153126498-26.9655956814-37.1813342187
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 176 )AA91 - 17660 - 145
33chain 'A' and (resid 177 through 215 )AA177 - 215146 - 184
44chain 'A' and (resid 216 through 388 )AA216 - 388185 - 357
55chain 'A' and (resid 389 through 421 )AA389 - 421358 - 390
67chain 'B' and (resid 32 through 136 )BK32 - 1361 - 105
78chain 'B' and (resid 137 through 176 )BK137 - 176106 - 145
89chain 'B' and (resid 177 through 215 )BK177 - 215146 - 184
910chain 'B' and (resid 216 through 289 )BK216 - 289185 - 258
1011chain 'B' and (resid 290 through 388 )BK290 - 388259 - 357
1112chain 'B' and (resid 389 through 423 )BK389 - 423358 - 392

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