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

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Basic information

Entry
Database: PDB / ID: 7prt
TitleCrystal structure of human heparanase in complex with covalent inhibitor CB678
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: 1.7 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 22, 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)53,87013
Polymers52,0072
Non-polymers1,86411
Water1,63991
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration, both subunits elute at a single peak at expected retention time
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area10850 Å2
ΔGint-48 kcal/mol
Surface area19110 Å2
MethodPISA
Unit cell
Length a, b, c (Å)46.808, 71.622, 78.739
Angle α, β, γ (deg.)90.000, 94.894, 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: 43733.324 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, 6 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-deoxy-alpha-D-arabino-hexopyranose-(1-4)-(2R,3S,5R,6R)-2,3,4,5,6-pentakis(oxidanyl)cyclohexane-1- ...2-deoxy-alpha-D-arabino-hexopyranose-(1-4)-(2R,3S,5R,6R)-2,3,4,5,6-pentakis(oxidanyl)cyclohexane-1-carboxylic acid


Type: oligosaccharide / Mass: 354.307 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
WURCS=2.0/1,1,0/[ad122h-1a_1-5_1*OC^RC^SC^RC^SC^SC^R$3/8O/7O/6O/5O/4CO/13=O]/1/WURCSPDB2Glycan 1.1.0
[][<C7O5>]{[(1+1)][a-D-2-deoxy-Glcp]{}}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.: 4 / 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, 96 molecules

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


Mass: 62.068 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C2H6O2
#7: Chemical ChemComp-CL / CHLORIDE ION / Chloride


Mass: 35.453 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Cl
#8: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 91 / 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: 2.52 Å3/Da / Density % sol: 51.1 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / Details: 0.1 M MES pH 5.5, 0.1 M MgCl2, 17% PEG 3350

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I03 / Wavelength: 0.979524 Å
DetectorType: DECTRIS EIGER2 XE 16M / Detector: PIXEL / Date: Feb 9, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.979524 Å / Relative weight: 1
ReflectionResolution: 1.7→78 Å / Num. obs: 56984 / % possible obs: 99.8 % / Redundancy: 4.1 % / CC1/2: 0.999 / Net I/σ(I): 11
Reflection shellResolution: 1.7→1.73 Å / Num. unique obs: 3015 / CC1/2: 0.748

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Processing

Software
NameVersionClassification
REFMAC5.8.0258refinement
DIALSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Starting model: 5.0E+98 / Resolution: 1.7→52.951 Å / Cor.coef. Fo:Fc: 0.969 / Cor.coef. Fo:Fc free: 0.951 / WRfactor Rfree: 0.238 / WRfactor Rwork: 0.192 / SU B: 4.445 / SU ML: 0.126 / Average fsc free: 0.7561 / Average fsc work: 0.7667 / Cross valid method: FREE R-VALUE / ESU R: 0.105 / ESU R Free: 0.109
Details: Hydrogens have been added in their riding positions
RfactorNum. reflection% reflection
Rfree0.2359 2800 4.92 %
Rwork0.1915 54110 -
all0.194 --
obs-56910 99.707 %
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: 38.659 Å2
Baniso -1Baniso -2Baniso -3
1-3.639 Å2-0 Å23.175 Å2
2---2.883 Å2-0 Å2
3----1.281 Å2
Refinement stepCycle: LAST / Resolution: 1.7→52.951 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3628 0 117 91 3836
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0090.0133890
X-RAY DIFFRACTIONr_bond_other_d0.0010.0173647
X-RAY DIFFRACTIONr_angle_refined_deg1.5931.6765283
X-RAY DIFFRACTIONr_angle_other_deg1.2991.6038480
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.9055466
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.15922.033182
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.79515652
X-RAY DIFFRACTIONr_dihedral_angle_4_deg14.9261521
X-RAY DIFFRACTIONr_chiral_restr0.0720.2503
X-RAY DIFFRACTIONr_gen_planes_refined0.0080.024264
X-RAY DIFFRACTIONr_gen_planes_other0.0020.02825
X-RAY DIFFRACTIONr_nbd_refined0.2140.2670
X-RAY DIFFRACTIONr_symmetry_nbd_other0.180.23232
X-RAY DIFFRACTIONr_nbtor_refined0.1660.21896
X-RAY DIFFRACTIONr_symmetry_nbtor_other0.0840.21652
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1320.2125
X-RAY DIFFRACTIONr_symmetry_nbd_refined0.2030.212
X-RAY DIFFRACTIONr_nbd_other0.2330.230
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_refined0.2020.24
X-RAY DIFFRACTIONr_mcbond_it2.9933.8241855
X-RAY DIFFRACTIONr_mcbond_other2.9933.8221854
X-RAY DIFFRACTIONr_mcangle_it4.1565.7222324
X-RAY DIFFRACTIONr_mcangle_other4.1555.7252325
X-RAY DIFFRACTIONr_scbond_it3.7264.3572035
X-RAY DIFFRACTIONr_scbond_other3.7284.352032
X-RAY DIFFRACTIONr_scangle_it5.5986.3612959
X-RAY DIFFRACTIONr_scangle_other5.5996.3592958
X-RAY DIFFRACTIONr_lrange_it7.14444.6934145
X-RAY DIFFRACTIONr_lrange_other7.15244.6734132
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.7-1.7440.3711980.3414010X-RAY DIFFRACTION99.4329
1.744-1.7920.3222120.3343854X-RAY DIFFRACTION99.608
1.792-1.8440.3241870.3233725X-RAY DIFFRACTION99.239
1.844-1.90.2831930.2853692X-RAY DIFFRACTION99.6665
1.9-1.9630.311790.2723563X-RAY DIFFRACTION99.7335
1.963-2.0320.2592050.2353417X-RAY DIFFRACTION99.8346
2.032-2.1080.2961630.2363325X-RAY DIFFRACTION99.8283
2.108-2.1940.2711920.2073160X-RAY DIFFRACTION99.8511
2.194-2.2920.2331690.2013057X-RAY DIFFRACTION99.8762
2.292-2.4040.2661560.1912954X-RAY DIFFRACTION99.8074
2.404-2.5330.2051230.1772808X-RAY DIFFRACTION99.66
2.533-2.6870.2351370.1842645X-RAY DIFFRACTION99.5705
2.687-2.8720.2731120.1872512X-RAY DIFFRACTION99.9619
2.872-3.1020.2281210.1912329X-RAY DIFFRACTION99.9592
3.102-3.3980.2411000.2042161X-RAY DIFFRACTION99.8675
3.398-3.7980.229970.1811940X-RAY DIFFRACTION99.9019
3.798-4.3830.1961010.1451700X-RAY DIFFRACTION99.8337
4.383-5.3640.171770.1291461X-RAY DIFFRACTION99.8053
5.364-7.5690.203560.1651136X-RAY DIFFRACTION100
7.569-520.22220.168661X-RAY DIFFRACTION99.4178

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