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- PDB-8k7g: Crystal structure of human lysosomal alpha-galactosidase A in com... -

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Basic information

Entry
Database: PDB / ID: 8k7g
TitleCrystal structure of human lysosomal alpha-galactosidase A in complex with (2R,3S,4R,5R)-2,5-bis(hydroxymethyl)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: 2.32 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)93,86413
Polymers90,7892
Non-polymers3,07511
Water9,746541
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5750 Å2
ΔGint-21 kcal/mol
Surface area30170 Å2
MethodPISA
Unit cell
Length a, b, c (Å)90.642, 90.642, 216.110
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 421 or resid 693 or resid 716 through 800))
d_2ens_1(chain "B" and (resid 32 through 421 or resid 692 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_12NAGNAGNAGNAGCC2
d_13NAGNAGNAGNAGDD2
d_14VMFVMFVMFVMFAG502
d_21LEULEUMETMETBB32 - 4211 - 390
d_22NAGNAGNAGNAGEE1
d_23NAGNAGNAGNAGBJ501
d_24VMFVMFVMFVMFBK502

NCS oper: (Code: givenMatrix: (-0.970466495122, -0.238694560571, -0.0349240404097), (-0.233761817926, 0.894734459974, 0.380533386991), (-0.0595835071543, 0.377458809526, -0.924107489845)Vector: 88. ...NCS oper: (Code: given
Matrix: (-0.970466495122, -0.238694560571, -0.0349240404097), (-0.233761817926, 0.894734459974, 0.380533386991), (-0.0595835071543, 0.377458809526, -0.924107489845)
Vector: 88.5176947119, 14.1949184726, -15.6665472426)

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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 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.: 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: 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, 547 molecules

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


Mass: 163.172 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C6H13NO4
#6: Chemical
ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: SO4
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 541 / 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: 56.43 %
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: 2.32→30 Å / Num. obs: 45211 / % possible obs: 99.9 % / Redundancy: 6.6 % / Biso Wilson estimate: 31.48 Å2 / Rmerge(I) obs: 0.123 / Net I/σ(I): 14.1
Reflection shellResolution: 2.32→2.4 Å / Rmerge(I) obs: 0.594 / Num. unique obs: 4380

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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: 2.32→29.67 Å / SU ML: 0.2447 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 22.7109
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2173 3677 4.83 %
Rwork0.1659 72476 -
obs0.1684 41311 89.02 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 39.81 Å2
Refinement stepCycle: LAST / Resolution: 2.32→29.67 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6261 0 198 550 7009
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00656629
X-RAY DIFFRACTIONf_angle_d0.93669004
X-RAY DIFFRACTIONf_chiral_restr0.0523966
X-RAY DIFFRACTIONf_plane_restr0.00791145
X-RAY DIFFRACTIONf_dihedral_angle_d15.45352426
Refine LS restraints NCSType: Torsion NCS / Rms dev position: 0.954440300978 Å
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.32-2.350.3362610.24341195X-RAY DIFFRACTION39.66
2.35-2.390.2663640.2391404X-RAY DIFFRACTION43.01
2.39-2.420.2786740.21631487X-RAY DIFFRACTION49.13
2.42-2.460.2981820.20741729X-RAY DIFFRACTION54.17
2.46-2.490.24331120.21992056X-RAY DIFFRACTION66.08
2.49-2.540.26811220.21062477X-RAY DIFFRACTION79.21
2.54-2.580.29661490.22222846X-RAY DIFFRACTION89.81
2.58-2.630.27641470.21572936X-RAY DIFFRACTION95.6
2.63-2.680.28521640.21083099X-RAY DIFFRACTION99.27
2.68-2.730.24471560.19823151X-RAY DIFFRACTION99.76
2.73-2.790.22691570.20193146X-RAY DIFFRACTION99.88
2.79-2.850.27431600.19253131X-RAY DIFFRACTION99.88
2.86-2.930.21841640.17763163X-RAY DIFFRACTION99.85
2.93-3.010.23221640.17853099X-RAY DIFFRACTION99.94
3.01-3.090.18681640.17693061X-RAY DIFFRACTION99.94
3.09-3.190.23921570.17323164X-RAY DIFFRACTION99.85
3.19-3.310.2381620.16163116X-RAY DIFFRACTION99.88
3.31-3.440.2281570.14763169X-RAY DIFFRACTION99.94
3.44-3.60.17661480.14113110X-RAY DIFFRACTION99.91
3.6-3.790.18631540.13783162X-RAY DIFFRACTION100
3.79-4.020.1751620.13293103X-RAY DIFFRACTION100
4.02-4.330.16081580.12373157X-RAY DIFFRACTION99.91
4.33-4.770.17451660.12343139X-RAY DIFFRACTION99.88
4.77-5.450.18581540.15273118X-RAY DIFFRACTION99.94
5.45-6.860.22771600.18553135X-RAY DIFFRACTION99.97
6.86-29.670.27381590.19263123X-RAY DIFFRACTION99.61
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)
10.2349312412430.0971877140245-0.0516010923170.0710434409440.06161727639640.1079928886770.05219376846080.0273248045092-0.1345954998830.0636500807937-0.05144355205480.1356399497540.103323241696-0.171813439772.35542851003E-50.228039259501-0.0258840641511-0.0168803917580.302900863824-0.002716711108460.25737930187126.5220650396-31.5549056399-5.04476544712
20.03805870319550.0175699705458-0.009291165153260.0308573070460.02437460368760.01468722932150.0396511382406-0.0636780900684-0.07809149247420.102602801003-0.1249078819820.1177827318680.124676224363-0.361347895931-3.24147367885E-50.211033419025-0.03641981646840.01269677660250.352865667675-0.000930850125560.2697217881415.7426875022-32.4876002847-1.98159434345
30.08784473675020.06116541104110.06231547497560.04915713766440.0760999078120.134692446590.0648716068819-0.2395029694980.240631738230.0717851071773-0.1985182628150.190876310871-0.139774284001-0.407579416584-0.004800002664610.263857827640.01435202154590.05845275777620.336383758361-0.03494293843180.35068088040721.1852245548-18.27906835797.54825504463
40.1254902842440.06994380351010.02856810443840.04894194636420.02232734805090.05254473183580.0696077451730.004735607500430.05777691292090.0675636560781-0.0493035326936-0.0596361929608-0.00137981001829-0.0903448417975-4.93434611959E-50.2152826065590.006510654178330.004363400126720.176936500737-4.3427543267E-50.19823519860940.7813589935-20.79775590442.94490473707
50.04264093974350.03786919857750.01050159726870.0472932886656-0.02058767351010.01850058637940.03704053759380.0190461722655-0.1050951535280.0717713776767-0.0212757652616-0.004168932062930.04942269963950.01820395484151.50687452875E-50.199497862820.03057322229670.002632558232190.223244663124-0.01026368060760.18713393129241.0028589707-34.4878279296-3.37537713537
60.1349459052030.03548943268520.1433087532220.02668755591360.0738929070160.1044269627050.0505149992754-0.0305009053060.07282202083170.007158513835190.01738147600220.02102919786810.1168384895830.06932574757931.34438054557E-50.2386298109190.0245404415444-0.0201014867680.2205242448630.02654157487520.20546948939356.8554038011-25.40552027367.25126227874
70.0699794161611-0.00542243921120.02915455776270.05046057716180.02415889113710.0151380242192-0.02958931162190.115843466304-0.1847177160060.05965302282710.143747073193-0.1838602993030.1265987503740.1234604918890.02356513928860.2456660652170.0940687975091-0.07402257394150.2822115417990.01560365313840.24215669931862.1399230085-31.86946418865.47153488634
80.312370565801-0.212589686179-0.003546884761880.186786323542-0.1319856668640.237524703657-0.001436723126630.2286572312850.06416013458780.0038371395342-0.179081281795-0.1917538466250.0328995137930.492022775459-0.1220270779110.2042608132570.03552143125940.01460511660010.4664855558630.1419166417420.34001285654973.9625744162-21.1417480705-25.3631096743
90.05628384741090.008974273574540.06588623654380.0101298464731-0.04157949101870.288938359632-0.2241426506660.261268698160.1790557153870.0193544835352-0.298054173876-0.298939774335-0.1393866098250.475064195871-0.3617064181870.271858776789-0.332920323899-0.04931327623520.5784242490780.4682554347540.63061519379776.5526335423-6.53081095801-27.9324000959
100.160166394875-0.06649949343280.01629155016610.17748751125-0.0495841696920.26303955321-0.3839880703970.265328843830.2948857313280.122517776935-0.29792135737-0.199016243417-0.2007241438640.42397931526-0.6731853171490.239855369588-0.3808901886730.08075988981770.2202043418630.5551151545370.34605613194368.0265162346-2.25895750515-33.7659919793
110.159146915146-0.02791374285480.1100897940450.130962505854-0.07341451627450.174431499475-0.03441260032490.03661286860940.06904091482190.0107185241901-0.0632309148774-0.0196421188616-0.1177688914870.0609256762614-0.1134824383340.2748131102320.007343151130690.004808940646880.1793719595130.0678181028840.23140051097953.7479796832-12.7863153353-28.6811733164
120.04484647800540.02093234455650.004921959004550.0152795836079-0.008476481114780.002048602059830.1303167947530.124985409073-0.109584405958-0.159374710281-0.0489625454904-0.1484856848130.1423543752550.06090382010410.0001110059763850.2394348225350.03900920607030.009151857175010.2240548126050.03745246374810.21923040455457.0786872758-27.4135222376-28.0366913245
130.1930956968720.04086637237020.1665770558880.1321239002670.01034971108550.1179877900150.0005349793600370.049510866040.121733689229-0.130503548640.002316589792120.09585214207570.0228589732681-0.0706494064389-0.01275063662360.2053126349790.0453775001008-0.006230764584240.2074461419260.04646685187290.12531030816339.0890442634-19.1308585516-35.2934534594
140.05631744152050.0175335002738-0.008535884315340.0406858904919-0.01934557984270.02160802078130.06211253673670.0877394556273-0.170171820246-0.154340613398-0.0244500973140.1167559289950.0932568386752-0.270565616319-0.001121889310670.301191290615-0.0173342288658-0.04663778680130.3275005842560.03134488420110.21453588658935.3330735865-27.2858925711-37.4740232186
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 100 )AA32 - 1001 - 69
22chain 'A' and (resid 101 through 136 )AA101 - 13670 - 105
33chain 'A' and (resid 137 through 215 )AA137 - 215106 - 184
44chain 'A' and (resid 216 through 289 )AA216 - 289185 - 258
55chain 'A' and (resid 290 through 320 )AA290 - 320259 - 289
66chain 'A' and (resid 321 through 388 )AA321 - 388290 - 357
77chain 'A' and (resid 389 through 421 )AA389 - 421358 - 390
88chain 'B' and (resid 32 through 136 )BJ32 - 1361 - 105
99chain 'B' and (resid 137 through 176 )BJ137 - 176106 - 145
1010chain 'B' and (resid 177 through 215 )BJ177 - 215146 - 184
1111chain 'B' and (resid 216 through 289 )BJ216 - 289185 - 258
1212chain 'B' and (resid 290 through 320 )BJ290 - 320259 - 289
1313chain 'B' and (resid 321 through 388 )BJ321 - 388290 - 357
1414chain 'B' and (resid 389 through 423 )BJ389 - 423358 - 392

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Related info.:EMDB / PDB / SASBDB / Comparison of 3 databanks / Yorodumi Search / Aug 31, 2016. New EM Navigator & Yorodumi / Yorodumi Papers / Jmol/JSmol / Function and homology information / Changes in new EM Navigator and Yorodumi

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