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- PDB-8k7k: Crystal structure of human lysosomal alpha-galactosidase A in com... -

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Basic information

Entry
Database: PDB / ID: 8k7k
TitleCrystal structure of human lysosomal alpha-galactosidase A in complex with (2R,3S,4R,5R)-2,5-bis(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 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)93,79612
Polymers90,7892
Non-polymers3,00710
Water14,178787
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5450 Å2
ΔGint-10 kcal/mol
Surface area30290 Å2
MethodPISA
Unit cell
Length a, b, c (Å)90.399, 90.399, 216.201
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

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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, 792 molecules

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


Mass: 177.198 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C7H15NO4 / Feature type: SUBJECT OF INVESTIGATION
#6: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: SO4
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 787 / 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: 2.8 Å3/Da / Density % sol: 56.15 %
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→30 Å / Num. obs: 69920 / % possible obs: 100 % / Redundancy: 12 % / Biso Wilson estimate: 26.65 Å2 / Rmerge(I) obs: 0.121 / Net I/σ(I): 20.8
Reflection shellResolution: 2→2.07 Å / Rmerge(I) obs: 0.942 / Num. unique obs: 6866

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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→29.59 Å / SU ML: 0.2147 / Cross valid method: FREE R-VALUE / σ(F): 1.37 / Phase error: 18.5356
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.1864 2003 2.98 %
Rwork0.1525 65179 -
obs0.1535 67182 96.2 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 32.17 Å2
Refinement stepCycle: LAST / Resolution: 2→29.59 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6261 0 204 792 7257
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00866662
X-RAY DIFFRACTIONf_angle_d0.96869045
X-RAY DIFFRACTIONf_chiral_restr0.0574970
X-RAY DIFFRACTIONf_plane_restr0.00861151
X-RAY DIFFRACTIONf_dihedral_angle_d14.09692447
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2-2.050.3046960.25863090X-RAY DIFFRACTION64.61
2.05-2.110.26561230.22214022X-RAY DIFFRACTION84.54
2.11-2.170.23821440.18624639X-RAY DIFFRACTION97.35
2.17-2.240.22581420.16784770X-RAY DIFFRACTION99.78
2.24-2.320.20331520.17244801X-RAY DIFFRACTION99.98
2.32-2.410.21021430.15564771X-RAY DIFFRACTION100
2.41-2.520.19791490.15254825X-RAY DIFFRACTION99.98
2.52-2.650.22031450.14764800X-RAY DIFFRACTION100
2.65-2.820.17341490.14924828X-RAY DIFFRACTION100
2.82-3.040.1781480.14164825X-RAY DIFFRACTION100
3.04-3.340.18021480.14994865X-RAY DIFFRACTION100
3.34-3.830.14621530.12834863X-RAY DIFFRACTION100
3.83-4.820.14731490.12174932X-RAY DIFFRACTION100
4.82-29.590.20051620.17565148X-RAY DIFFRACTION99.89
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)
10.149927750285-0.0202770779517-0.0963270706240.07643871165970.003509953770890.1430176281620.05325879961550.0242991959164-0.07650097016620.00555207196745-0.01267307030820.1241647269830.111717646546-0.1875760464360.01015856135680.181946314172-0.0567583794618-0.008839113435090.1996335684480.003215292733570.19458583650726.3866767044-31.2663401674-4.94247629467
20.02072283302290.0242019284491-0.01074650766280.02967817258490.003551581205410.02612550749550.02528985596170.00479582177128-0.009936849275390.01638933763-0.0206780862870.1435746790570.0405654628872-0.2606580841310.0007797871937140.183185236486-0.054024894784-0.008601005193360.252262496251-0.0006792954155050.24955711211215.5059791728-32.1646593088-1.96048711869
30.2532011000730.06821344659660.2503997221240.04571730155170.06954105840260.3517009489960.0577033904957-0.2172933145760.1716545393450.0629647510913-0.1318140090820.198515130355-0.0867420853805-0.343066532164-0.09181451698140.198755623658-0.002691333627120.06992313317370.246620956372-0.04401907614470.25706948042121.0660009374-17.91724633467.50145005473
40.04864743560270.006830136301560.01558766353560.00335156577790.003377430969880.00540471142464-0.0119362130425-0.0375533565740.09170935695980.0259678521202-0.07137005280220.1096254797580.00721264376762-0.0664154087152-0.01182191993470.191167259822-0.01757699739170.02942761187870.149951037545-0.02487928928210.13715801023933.5648187999-18.39441774467.4587042782
50.0111650781879-0.002391224945580.01324239642510.00161660488342-0.0005615587621210.01366381905470.009870521588270.006625700517820.07808487392020.0780477990662-0.04011901680220.00458645294688-0.0280789670675-0.0800095290333-5.30531384385E-50.203362549916-0.02632008752640.003341935044360.141286733528-0.0004071203089090.17481530907942.8387139391-17.10335522156.26720325476
60.05903682080140.04304689378580.05482328631730.03270411273620.04156542991320.05686614406720.03084696417590.0910970767896-0.030671985101-0.006870972886730.06547157717120.004285710022090.0462775213654-0.03157077693250.01667221081470.168429027029-0.01711266158270.003794057226150.1446011968640.01210126795950.14860834789844.2796971842-26.6943959304-5.13783154494
70.03223801461680.004288451571420.008322708236780.005715000812670.00312726363340.006803012088030.02888043265160.0749147894657-0.1032092669910.0465454993917-0.0158391772323-0.003595103032430.118270235782-0.00421608559281-0.0003556727791140.14150027561-0.0205285426844-0.01079069197890.110104820676-0.01005890231940.1324248364540.7160586165-34.3225223934-3.26168261476
80.0556777816917-0.01784314047270.01804453818280.05121052380880.03675779785720.0323849470560.03241835900470.007344761907350.02121458222520.0875637744573-0.0221837716204-0.07560708916730.09525302499020.06015128682990.0004661016525950.197113962673-0.0234153781018-0.02127130684630.1816278161420.01956605945830.15245847154356.5531625816-25.30576153297.24084834477
90.0366938318767-0.01523046855840.03424412521260.0104504455274-0.006052644249390.03232242227130.009087995038050.0309084344316-0.04836356428210.101314131580.0780937823554-0.1402198053940.06725716636290.105245744850.004357414746630.240962171050.0399864061388-0.0474686527590.1985577353410.0006705540681260.1768682156961.7965104335-31.85480380625.61893706013
109.530729129621.99999814256-7.673511907752.0000067952.0000014782.000001727470.07037431578910.06624796545070.150126220446-0.475255352087-0.06898433402210.239920664192-0.0102413785270.02465956761210.0001906154461081.09141846704-0.0307691009898-0.03608840304041.107034605320.01169456377691.1046043620856.7241275454-39.741403335521.0143316385
110.0674295496326-0.00693970252956-0.06359841759950.147535647855-0.0008520663151680.1260558107150.008726515625140.1985695120060.0508743905726-0.0176658191283-0.160686651631-0.3198421131080.04340418908460.365450016866-0.04229507557130.1923097386070.02909543525350.0294441970720.3579399380740.1222715784090.33623179432973.6461935147-21.4660584978-25.5012589669
120.0786259216218-0.01309935954910.04136143201810.0216263917843-0.04212756736850.0881595396859-0.1014993872660.1809222576870.184743742167-0.00597302553523-0.144711519023-0.255390119242-0.09869405318880.273460794696-0.6035464353070.197051485536-0.2016798080810.0551258979630.2984931172110.4033782272620.51092490839772.1776162087-4.71555863924-31.2787058382
130.117218579766-0.05723997416070.04332192912650.05643796796370.02548783146140.0998144427047-0.02390362016030.08359821678620.161063581004-0.0326320122506-0.0817885545858-0.0982950288007-0.04941452963550.102209755721-0.215895464810.205705733243-0.00444846473650.01141266451120.1772892348220.07147580314170.19620225613753.6024340605-12.9451788972-28.807546048
140.0182184195501-0.00312045854017-0.008464086088020.00217197171666-0.001813341792760.006730932525680.04985862343110.0504594537153-0.134922602421-0.0808389391557-0.0203556666412-0.09211997679110.06806201536630.04995308684670.0002069973929290.1940126922810.03065399227320.01668396998880.1685452029750.03177401460190.17668338899456.6038488009-27.7018113483-27.9989228829
150.07368799987050.08943378488240.04288877047680.1547846650490.08570224973760.1170101315050.03539964899660.1416598025610.0513948284765-0.201300924169-0.03146211106480.147737022520.0610897795411-0.122946034713-0.01286119006420.2430054563480.0203451467941-0.02518870904270.226952506110.04422060210240.13946656966338.8672801453-19.1872864736-35.3373004905
160.02110383440770.003365622259490.001004154331370.007187249215340.00337633827660.00249415421220.09442966309430.133728075273-0.0286740260468-0.1209997797020.02516621661440.166985496599-0.0407262309496-0.1621187921380.0006562556635350.264910958724-0.0195110611742-0.06445876175770.26989057070.03027346188830.20089855485735.0052707412-27.2710637562-37.5177363508
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 235 )AA216 - 235185 - 204
55chain 'A' and (resid 236 through 264 )AA236 - 264205 - 233
66chain 'A' and (resid 265 through 289 )AA265 - 289234 - 258
77chain 'A' and (resid 290 through 320 )AA290 - 320259 - 289
88chain 'A' and (resid 321 through 388 )AA321 - 388290 - 357
99chain 'A' and (resid 389 through 421 )AA389 - 421358 - 390
1010chain 'A' and (resid 422 through 422 )AB4221
1111chain 'B' and (resid 32 through 136 )BK32 - 1361 - 105
1212chain 'B' and (resid 137 through 215 )BK137 - 215106 - 184
1313chain 'B' and (resid 216 through 289 )BK216 - 289185 - 258
1414chain 'B' and (resid 290 through 320 )BK290 - 320259 - 289
1515chain 'B' and (resid 321 through 388 )BK321 - 388290 - 357
1616chain 'B' and (resid 389 through 423 )BK389 - 423358 - 392

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