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- PDB-8ohq: Crystal structure of human heparanase in complex with competitive... -

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Basic information

Entry
Database: PDB / ID: 8ohq
TitleCrystal structure of human heparanase in complex with competitive inhibitor derrived from siastatin B
Components
  • Heparanase 50 kDa subunit
  • Heparanase 8 kDa subunit
KeywordsHYDROLASE / Inhibitor / Complex
Function / homology
Function and homology information


heparanase / heparanase activity / regulation of hair follicle development / heparin metabolic process / proteoglycan metabolic process / heparan sulfate proteoglycan catabolic process / beta-glucuronidase activity / positive regulation of hair follicle development / HS-GAG degradation / protein transmembrane transport ...heparanase / heparanase activity / regulation of hair follicle development / heparin metabolic process / proteoglycan metabolic process / heparan sulfate proteoglycan catabolic process / beta-glucuronidase activity / positive regulation of hair follicle development / HS-GAG degradation / protein transmembrane transport / 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 / cell-matrix adhesion / : / extracellular matrix / specific granule lumen / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / lysosome / 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
Chem-VGO / Heparanase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.7 Å
AuthorsWu, L. / Davies, G.J. / Overkleeft, H.S. / Armstrong, Z. / Yurong, C.
Funding support Netherlands, European Union, United Kingdom, 6items
OrganizationGrant numberCountry
Netherlands Organisation for Scientific Research (NWO)VI.Veni.212.173 Netherlands
European Research Council (ERC)ERC-2011-AdG-290836European Union
European Research Council (ERC)ERC-2012-AdG-32294European Union
European Research Council (ERC)ERC-2020-SyG-951231European Union
Biotechnology and Biological Sciences Research Council (BBSRC)BB/R001162/1 United Kingdom
Biotechnology and Biological Sciences Research Council (BBSRC)BB/M011151/1 United Kingdom
CitationJournal: J.Am.Chem.Soc. / Year: 2024
Title: Molecular Basis for Inhibition of Heparanases and beta-Glucuronidases by Siastatin B.
Authors: Chen, Y. / van den Nieuwendijk, A.M.C.H. / Wu, L. / Moran, E. / Skoulikopoulou, F. / van Riet, V. / Overkleeft, H.S. / Davies, G.J. / Armstrong, Z.
History
DepositionMar 21, 2023Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jan 10, 2024Provider: repository / Type: Initial release
Revision 1.1Jan 24, 2024Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.year / _citation_author.identifier_ORCID

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
AAA: Heparanase 50 kDa subunit
BBB: Heparanase 8 kDa subunit
hetero molecules


Theoretical massNumber of molelcules
Total (without water)53,33014
Polymers51,6082
Non-polymers1,72212
Water4,486249
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area11150 Å2
ΔGint-64 kcal/mol
Surface area19020 Å2
Unit cell
Length a, b, c (Å)46.110, 70.920, 78.560
Angle α, β, γ (deg.)90.000, 95.530, 90.000
Int Tables number4
Space group name H-MP1211

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Components

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Protein , 2 types, 2 molecules AAABBB

#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 , 2 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-ROHGlycam 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
[][D-1-deoxy-GlcpNAc]{[(6+1)][a-L-Fucp]{}}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.: 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 , 4 types, 256 molecules

#5: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


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


Mass: 35.453 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: Cl
#7: Chemical ChemComp-VGO / (3~{S},4~{S})-4,5,5-tris(oxidanyl)piperidine-3-carboxylic acid


Mass: 177.155 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C6H11NO5 / Feature type: SUBJECT OF INVESTIGATION
#8: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 249 / 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: 2.48 Å3/Da / Density % sol: 50.35 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 5.5 / 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: I04 / Wavelength: 0.91733 Å
DetectorType: DECTRIS PILATUS 6M-F / Detector: PIXEL / Date: May 24, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.91733 Å / Relative weight: 1
ReflectionResolution: 1.7→45.938 Å / Num. obs: 55285 / % possible obs: 99.6 % / Redundancy: 1.9 % / CC1/2: 0.998 / Net I/σ(I): 10.8
Reflection shellResolution: 1.7→1.73 Å / Num. unique obs: 2968 / CC1/2: 0.598

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Processing

Software
NameVersionClassification
REFMAC5.8.0258refinement
xia2data reduction
xia2data scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.7→45.938 Å / Cor.coef. Fo:Fc: 0.968 / Cor.coef. Fo:Fc free: 0.958 / WRfactor Rfree: 0.207 / WRfactor Rwork: 0.173 / SU B: 2.427 / SU ML: 0.078 / Average fsc free: 0.9162 / Average fsc work: 0.9249 / Cross valid method: FREE R-VALUE / ESU R: 0.1 / ESU R Free: 0.1
Details: Hydrogens have been added in their riding positions
RfactorNum. reflection% reflection
Rfree0.2077 2756 4.985 %
Rwork0.1743 52528 -
all0.176 --
obs-55284 99.566 %
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: 28.937 Å2
Baniso -1Baniso -2Baniso -3
1-1.357 Å20 Å20.28 Å2
2---0.658 Å2-0 Å2
3----0.739 Å2
Refinement stepCycle: LAST / Resolution: 1.7→45.938 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3640 0 107 249 3996
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.010.0133874
X-RAY DIFFRACTIONr_bond_other_d0.0050.0173644
X-RAY DIFFRACTIONr_angle_refined_deg1.651.6765258
X-RAY DIFFRACTIONr_angle_other_deg1.4781.6048466
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.8095465
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.79521.913183
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.45315655
X-RAY DIFFRACTIONr_dihedral_angle_4_deg12.751522
X-RAY DIFFRACTIONr_chiral_restr0.0810.2497
X-RAY DIFFRACTIONr_chiral_restr_other0.4940.21
X-RAY DIFFRACTIONr_gen_planes_refined0.010.024255
X-RAY DIFFRACTIONr_gen_planes_other0.0030.02825
X-RAY DIFFRACTIONr_nbd_refined0.210.2693
X-RAY DIFFRACTIONr_symmetry_nbd_other0.1920.23210
X-RAY DIFFRACTIONr_nbtor_refined0.170.21883
X-RAY DIFFRACTIONr_symmetry_nbtor_other0.0850.21603
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1420.2201
X-RAY DIFFRACTIONr_symmetry_nbd_refined0.3540.214
X-RAY DIFFRACTIONr_nbd_other0.1920.246
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_refined0.2590.26
X-RAY DIFFRACTIONr_xyhbond_nbd_other0.1710.21
X-RAY DIFFRACTIONr_mcbond_it2.6072.7151854
X-RAY DIFFRACTIONr_mcbond_other2.6072.7121853
X-RAY DIFFRACTIONr_mcangle_it3.9174.0582321
X-RAY DIFFRACTIONr_mcangle_other3.9164.0612322
X-RAY DIFFRACTIONr_scbond_it3.5143.2922020
X-RAY DIFFRACTIONr_scbond_other3.5143.2922021
X-RAY DIFFRACTIONr_scangle_it5.3724.752937
X-RAY DIFFRACTIONr_scangle_other5.3714.752938
X-RAY DIFFRACTIONr_lrange_it7.1332.9824235
X-RAY DIFFRACTIONr_lrange_other7.1232.7764192
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.7-1.7440.2962050.2783887X-RAY DIFFRACTION99.8049
1.744-1.7920.2931830.2683797X-RAY DIFFRACTION99.7494
1.792-1.8440.3061690.2483701X-RAY DIFFRACTION99.8967
1.844-1.90.2732030.2263516X-RAY DIFFRACTION99.5716
1.9-1.9630.2331890.1933475X-RAY DIFFRACTION99.7278
1.963-2.0320.21870.1863303X-RAY DIFFRACTION99.8284
2.032-2.1080.2441650.1883257X-RAY DIFFRACTION99.7086
2.108-2.1940.2091870.1773085X-RAY DIFFRACTION99.7561
2.194-2.2920.1841600.1682989X-RAY DIFFRACTION99.8731
2.292-2.4040.2341350.1642834X-RAY DIFFRACTION99.6643
2.404-2.5330.211430.1652735X-RAY DIFFRACTION99.7574
2.533-2.6870.2261290.1692565X-RAY DIFFRACTION99.7778
2.687-2.8720.2131240.1662428X-RAY DIFFRACTION99.5708
2.872-3.1020.2251150.1752252X-RAY DIFFRACTION99.2453
3.102-3.3970.2241050.1822065X-RAY DIFFRACTION98.9964
3.397-3.7980.171050.1631857X-RAY DIFFRACTION98.8413
3.798-4.3830.146880.1361659X-RAY DIFFRACTION99.3743
4.383-5.3640.178820.1421391X-RAY DIFFRACTION98.9919
5.364-7.5680.23570.1781099X-RAY DIFFRACTION98.8034
7.568-45.9380.17250.17633X-RAY DIFFRACTION98.6507

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