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- PDB-7pr8: Crystal structure of human heparanase in complex with covalent in... -

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Basic information

Entry
Database: PDB / ID: 7pr8
TitleCrystal structure of human heparanase in complex with covalent inhibitor GR109
Components
  • Heparanase 50 kDa subunit
  • Heparanase 8 kDa subunit
KeywordsCARBOHYDRATE / glycoside hydrolase / glucuronidase / GH79 / heparan sulfate
Function / homology
Function and homology information


heparanase / heparanase activity / regulation of hair follicle development / heparin metabolic process / beta-glucuronidase activity / heparan sulfate proteoglycan catabolic process / proteoglycan metabolic process / protein transmembrane transport / HS-GAG degradation / positive regulation of hair follicle development ...heparanase / heparanase activity / regulation of hair follicle development / heparin metabolic process / beta-glucuronidase activity / heparan sulfate proteoglycan catabolic process / proteoglycan metabolic process / protein transmembrane transport / HS-GAG degradation / positive regulation of hair follicle development / syndecan binding / vascular wound healing / angiogenesis involved in wound healing / establishment of endothelial barrier / positive regulation of osteoblast proliferation / positive regulation of vascular endothelial growth factor production / positive regulation of blood coagulation / lysosomal lumen / extracellular matrix / cell-matrix adhesion / response to organic substance / specific granule lumen / lysosome / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / membrane raft / lysosomal membrane / intracellular membrane-bounded organelle / Neutrophil degranulation / extracellular space / extracellular region / nucleoplasm / nucleus
Similarity search - Function
Glycoside hydrolase, family 79 / Glycosyl hydrolase family 79, N-terminal domain / Glycoside hydrolase superfamily
Similarity search - Domain/homology
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.66 Å
AuthorsWu, L. / Armstrong, Z. / Davies, G.J.
Funding support United Kingdom, 7items
OrganizationGrant numberCountry
European Research Council (ERC)ERC-2011-AdG-290836 United Kingdom
European Research Council (ERC)ERC-2012-AdG-322942 United Kingdom
Netherlands Organisation for Scientific Research (NWO) United Kingdom
Israel Science Foundation1021/19 United Kingdom
European Molecular Biology Organization (EMBO)STF8184 United Kingdom
Royal Society United Kingdom
Wellcome Trust218579/Z/19/Z United Kingdom
CitationJournal: Proc.Natl.Acad.Sci.USA / Year: 2022
Title: Mechanism-based heparanase inhibitors reduce cancer metastasis in vivo.
Authors: de Boer, C. / Armstrong, Z. / Lit, V.A.J. / Barash, U. / Ruijgrok, G. / Boyango, I. / Weitzenberg, M.M. / Schroder, S.P. / Sarris, A.J.C. / Meeuwenoord, N.J. / Bule, P. / Kayal, Y. / Ilan, N. ...Authors: de Boer, C. / Armstrong, Z. / Lit, V.A.J. / Barash, U. / Ruijgrok, G. / Boyango, I. / Weitzenberg, M.M. / Schroder, S.P. / Sarris, A.J.C. / Meeuwenoord, N.J. / Bule, P. / Kayal, Y. / Ilan, N. / Codee, J.D.C. / Vlodavsky, I. / Overkleeft, H.S. / Davies, G.J. / Wu, L.
History
DepositionSep 21, 2021Deposition site: PDBE / Processing site: PDBE
Revision 1.0Aug 3, 2022Provider: repository / Type: Initial release
Revision 1.1Jan 31, 2024Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Heparanase 50 kDa subunit
B: Heparanase 8 kDa subunit
hetero molecules


Theoretical massNumber of molelcules
Total (without water)53,53914
Polymers51,6082
Non-polymers1,93012
Water5,549308
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration, both subunits elute in a single peak at the expected retention time
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area10990 Å2
ΔGint-29 kcal/mol
Surface area19180 Å2
MethodPISA
Unit cell
Length a, b, c (Å)46.490, 71.290, 79.070
Angle α, β, γ (deg.)90.000, 95.200, 90.000
Int Tables number4
Space group name H-MP1211

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Components

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Protein , 2 types, 2 molecules AB

#1: Protein Heparanase 50 kDa subunit


Mass: 43334.898 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: HPSE, HEP, HPA, HPA1, HPR1, HPSE1, HSE1 / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: Q9Y251
#2: Protein Heparanase 8 kDa subunit


Mass: 8273.514 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: HPSE, HEP, HPA, HPA1, HPR1, HPSE1, HSE1 / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: Q9Y251

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Sugars , 3 types, 5 molecules

#3: Polysaccharide alpha-L-fucopyranose-(1-6)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 367.349 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
LFucpa1-6DGlcpNAcb1-Glycam Condensed SequenceGMML 1.0
WURCS=2.0/2,2,1/[a2122h-1b_1-5_2*NCC/3=O][a1221m-1a_1-5]/1-2/a6-b1WURCSPDB2Glycan 1.1.0
[]{[(4+1)][b-D-GlcpNAc]{[(6+1)][a-L-Fucp]{}}}LINUCSPDB-CARE
#4: Polysaccharide 2-acetamido-2-deoxy-6-O-sulfo-alpha-D-glucopyranose-(1-4)-(2R,3S,5R,6R)-2,3,4,5,6-pentakis(oxidanyl) ...2-acetamido-2-deoxy-6-O-sulfo-alpha-D-glucopyranose-(1-4)-(2R,3S,5R,6R)-2,3,4,5,6-pentakis(oxidanyl)cyclohexane-1-carboxylic acid


Type: oligosaccharide / Mass: 491.422 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
WURCS=2.0/1,1,0/[a2122h-1a_1-5_1*OC^RC^SC^RC^SC^SC^R$3/8O/7O/6O/5O/4CO/13=O_2*NCC/3=O_6*OSO/3=O/3=O]/1/WURCSPDB2Glycan 1.1.0
[][<C7O5>]{[(1+1)][a-D-GlcpNAc6SO3]{}}LINUCSPDB-CARE
#5: 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 / N-Acetylglucosamine


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, 315 molecules

#6: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL / Ethylene glycol


Mass: 62.068 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: C2H6O2
#7: Chemical ChemComp-CL / CHLORIDE ION / Chloride


Mass: 35.453 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Cl
#8: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 308 / 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: 2.53 Å3/Da / Density % sol: 51.35 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / Details: 0.1 M MES pH 5.5, 0.1 M MgCl2, 17% PEG3350

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I03 / Wavelength: 0.97933 Å
DetectorType: DECTRIS EIGER2 XE 16M / Detector: PIXEL / Date: Nov 30, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97933 Å / Relative weight: 1
ReflectionResolution: 1.66→39.37 Å / Num. obs: 59928 / % possible obs: 98.6 % / Redundancy: 4.2 % / CC1/2: 0.999 / Rmerge(I) obs: 0.052 / Rpim(I) all: 0.029 / Net I/σ(I): 12.5
Reflection shellResolution: 1.66→1.7 Å / Rmerge(I) obs: 1.415 / Mean I/σ(I) obs: 1 / Num. unique obs: 4353 / CC1/2: 0.532 / Rpim(I) all: 0.789

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Processing

Software
NameVersionClassification
REFMAC5.8.0267refinement
xia2data reduction
Aimlessdata scaling
REFMACphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5e8m

5e8m


Resolution: 1.66→39.37 Å / Cor.coef. Fo:Fc: 0.976 / Cor.coef. Fo:Fc free: 0.967 / SU B: 2.738 / SU ML: 0.084 / Cross valid method: FREE R-VALUE / ESU R: 0.091 / ESU R Free: 0.089
Details: Hydrogens have been added in their riding positions
RfactorNum. reflection% reflection
Rfree0.1943 3027 5.052 %
Rwork0.1666 56894 -
all0.168 --
obs-59921 98.579 %
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK BULK SOLVENT
Displacement parametersBiso mean: 36.497 Å2
Baniso -1Baniso -2Baniso -3
1-2.611 Å2-0 Å21.759 Å2
2---2.022 Å20 Å2
3----0.894 Å2
Refinement stepCycle: LAST / Resolution: 1.66→39.37 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3643 0 122 308 4073
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.010.0133932
X-RAY DIFFRACTIONr_bond_other_d0.0010.0173749
X-RAY DIFFRACTIONr_angle_refined_deg1.6941.6965342
X-RAY DIFFRACTIONr_angle_other_deg1.3751.6188665
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.8095467
X-RAY DIFFRACTIONr_dihedral_angle_2_deg33.12121.858183
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.13515654
X-RAY DIFFRACTIONr_dihedral_angle_4_deg11.0931522
X-RAY DIFFRACTIONr_chiral_restr0.280.2515
X-RAY DIFFRACTIONr_gen_planes_refined0.0090.024850
X-RAY DIFFRACTIONr_gen_planes_other0.0030.02904
X-RAY DIFFRACTIONr_nbd_refined0.2050.2740
X-RAY DIFFRACTIONr_symmetry_nbd_other0.1780.23475
X-RAY DIFFRACTIONr_nbtor_refined0.1710.21907
X-RAY DIFFRACTIONr_symmetry_nbtor_other0.0870.21821
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1590.2242
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_other0.040.24
X-RAY DIFFRACTIONr_symmetry_nbd_refined0.1750.219
X-RAY DIFFRACTIONr_nbd_other0.2480.261
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_refined0.2170.212
X-RAY DIFFRACTIONr_mcbond_it2.9213.4711859
X-RAY DIFFRACTIONr_mcbond_other2.9173.4681858
X-RAY DIFFRACTIONr_mcangle_it3.9325.1892329
X-RAY DIFFRACTIONr_mcangle_other3.9335.1912330
X-RAY DIFFRACTIONr_scbond_it4.0954.0132073
X-RAY DIFFRACTIONr_scbond_other4.0944.0142074
X-RAY DIFFRACTIONr_scangle_it6.0875.8183013
X-RAY DIFFRACTIONr_scangle_other6.0865.823014
X-RAY DIFFRACTIONr_lrange_it7.60642.0124323
X-RAY DIFFRACTIONr_lrange_other7.60642.0214324
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.66-1.7030.3432410.3324104X-RAY DIFFRACTION97.7283
1.703-1.750.3342010.3114065X-RAY DIFFRACTION98.0239
1.75-1.80.2831900.2834004X-RAY DIFFRACTION98.1971
1.8-1.8560.282070.2443836X-RAY DIFFRACTION98.2264
1.856-1.9170.2412110.2083696X-RAY DIFFRACTION98.2893
1.917-1.9840.2342000.23608X-RAY DIFFRACTION98.271
1.984-2.0590.2191610.1713518X-RAY DIFFRACTION98.8182
2.059-2.1430.1971560.1673406X-RAY DIFFRACTION98.7251
2.143-2.2380.2111820.1573207X-RAY DIFFRACTION98.4316
2.238-2.3470.2231560.1583094X-RAY DIFFRACTION98.9044
2.347-2.4740.1791750.1542938X-RAY DIFFRACTION98.6063
2.474-2.6240.1781750.1542766X-RAY DIFFRACTION99.1571
2.624-2.8050.2091540.1632599X-RAY DIFFRACTION98.922
2.805-3.0290.2081230.1642474X-RAY DIFFRACTION99.1979
3.029-3.3180.1861260.1672271X-RAY DIFFRACTION99.2958
3.318-3.7080.2960.1682042X-RAY DIFFRACTION98.8442
3.708-4.2810.1541110.1321812X-RAY DIFFRACTION99.4827
4.281-5.2390.128760.1271556X-RAY DIFFRACTION99.4516
5.239-7.3920.206530.1741207X-RAY DIFFRACTION99.5261
7.392-39.370.162330.154691X-RAY DIFFRACTION98.9071

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