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- PDB-8ohr: Crystal structure of human heparanase in complex with glucuronic ... -

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Basic information

Entry
Database: PDB / ID: 8ohr
TitleCrystal structure of human heparanase in complex with glucuronic acid configured 3-geminal diol iminosugar inhibitor
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 proteoglycan metabolic process / heparan sulfate proteoglycan catabolic process / beta-glucuronidase activity / HS-GAG degradation / positive regulation of hair follicle development / syndecan binding / proteoglycan metabolic process ...heparanase / heparanase activity / regulation of hair follicle development / heparin proteoglycan metabolic process / heparan sulfate proteoglycan catabolic process / beta-glucuronidase activity / HS-GAG degradation / positive regulation of hair follicle development / syndecan binding / proteoglycan metabolic process / vascular wound healing / protein transmembrane transport / establishment of endothelial barrier / angiogenesis involved in wound healing / positive regulation of osteoblast proliferation / positive regulation of vascular endothelial growth factor production / positive regulation of blood coagulation / extracellular matrix / lysosomal lumen / cell-matrix adhesion / specific granule lumen / lysosome / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / membrane raft / lysosomal membrane / response to antibiotic / 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-VP5 / Heparanase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.8 Å
AuthorsArmstrong, Z. / Yurong, C. / Wu, L. / Overkleeft, H.S. / Davies, G.J.
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
Revision 1.2Oct 9, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature / Item: _pdbx_entry_details.has_protein_modification

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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)52,2288
Polymers51,6082
Non-polymers6206
Water3,279182
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area9260 Å2
ΔGint-55 kcal/mol
Surface area18370 Å2
Unit cell
Length a, b, c (Å)44.436, 71.080, 78.232
Angle α, β, γ (deg.)90.000, 98.433, 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 , 1 types, 1 molecules

#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


Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 1 / 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, 187 molecules

#3: Chemical ChemComp-VP5 / (3~{S},4~{R})-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
#4: 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.: 1 / Source method: obtained synthetically / Formula: Cl
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 182 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestY
Has protein modificationY

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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: 2.37 Å3/Da / Density % sol: 48.06 %
Crystal growTemperature: 293 K / Method: vapor diffusion / 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: 0.979499 Å
DetectorType: DECTRIS EIGER2 X 16M / Detector: PIXEL / Date: Feb 18, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.979499 Å / Relative weight: 1
ReflectionResolution: 1.8→43.994 Å / Num. obs: 44493 / % possible obs: 99.1 % / Redundancy: 4.6 % / CC1/2: 0.993 / Net I/σ(I): 8.8
Reflection shellResolution: 1.8→1.84 Å / Mean I/σ(I) obs: 1.4 / Num. unique obs: 2569 / CC1/2: 0.606

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Processing

Software
NameVersionClassification
REFMAC5.8.0258refinement
DIALSdata reduction
DIALSdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.8→43.994 Å / Cor.coef. Fo:Fc: 0.962 / Cor.coef. Fo:Fc free: 0.942 / WRfactor Rfree: 0.213 / WRfactor Rwork: 0.178 / SU B: 3.218 / SU ML: 0.095 / Average fsc free: 0.8907 / Average fsc work: 0.907 / Cross valid method: FREE R-VALUE / ESU R: 0.126 / ESU R Free: 0.12
Details: Hydrogens have been added in their riding positions
RfactorNum. reflection% reflection
Rfree0.2164 2225 5.012 %
Rwork0.1798 42171 -
all0.182 --
obs-44396 99.2 %
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: 29.174 Å2
Baniso -1Baniso -2Baniso -3
1-0.333 Å20 Å20.543 Å2
2---1.6 Å2-0 Å2
3---1.06 Å2
Refinement stepCycle: LAST / Resolution: 1.8→43.994 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3617 0 39 182 3838
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.010.0133770
X-RAY DIFFRACTIONr_bond_other_d0.0010.0173564
X-RAY DIFFRACTIONr_angle_refined_deg1.651.6495109
X-RAY DIFFRACTIONr_angle_other_deg1.3661.5828272
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.9925461
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.97622.011179
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.32815648
X-RAY DIFFRACTIONr_dihedral_angle_4_deg18.0561521
X-RAY DIFFRACTIONr_chiral_restr0.0780.2473
X-RAY DIFFRACTIONr_chiral_restr_other0.0290.21
X-RAY DIFFRACTIONr_gen_planes_refined0.0090.024162
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02803
X-RAY DIFFRACTIONr_nbd_refined0.2110.2729
X-RAY DIFFRACTIONr_symmetry_nbd_other0.190.23318
X-RAY DIFFRACTIONr_nbtor_refined0.170.21859
X-RAY DIFFRACTIONr_symmetry_nbtor_other0.0830.21658
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1670.2189
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_other0.1340.22
X-RAY DIFFRACTIONr_symmetry_nbd_refined0.2160.215
X-RAY DIFFRACTIONr_nbd_other0.2890.248
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_refined0.1850.29
X-RAY DIFFRACTIONr_mcbond_it2.4892.8521841
X-RAY DIFFRACTIONr_mcbond_other2.4692.851840
X-RAY DIFFRACTIONr_mcangle_it3.5664.2682303
X-RAY DIFFRACTIONr_mcangle_other3.5654.2722304
X-RAY DIFFRACTIONr_scbond_it3.3173.2451929
X-RAY DIFFRACTIONr_scbond_other3.3153.2361926
X-RAY DIFFRACTIONr_scangle_it4.994.7022806
X-RAY DIFFRACTIONr_scangle_other4.994.72805
X-RAY DIFFRACTIONr_lrange_it6.69134.2114202
X-RAY DIFFRACTIONr_lrange_other6.64734.134182
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.8-1.8470.3161700.2783076X-RAY DIFFRACTION98.3935
1.847-1.8970.2971590.2382991X-RAY DIFFRACTION98.4991
1.897-1.9520.2481520.232952X-RAY DIFFRACTION98.7591
1.952-2.0120.2141520.1962848X-RAY DIFFRACTION98.7167
2.012-2.0780.2721510.2262737X-RAY DIFFRACTION98.9719
2.078-2.1510.2181570.2032659X-RAY DIFFRACTION98.7724
2.151-2.2320.1911560.1722578X-RAY DIFFRACTION99.2378
2.232-2.3230.2441280.1682497X-RAY DIFFRACTION99.3942
2.323-2.4270.1921250.1642376X-RAY DIFFRACTION99.5225
2.427-2.5450.2261140.1692304X-RAY DIFFRACTION99.2204
2.545-2.6820.223980.172202X-RAY DIFFRACTION99.7398
2.682-2.8450.2021240.1622057X-RAY DIFFRACTION99.6345
2.845-3.0410.175850.1551964X-RAY DIFFRACTION99.8052
3.041-3.2840.219990.181822X-RAY DIFFRACTION99.948
3.284-3.5970.211760.1741690X-RAY DIFFRACTION99.9434
3.597-4.020.191910.1761518X-RAY DIFFRACTION99.9379
4.02-4.640.212580.1541353X-RAY DIFFRACTION99.7878
4.64-5.6780.189570.1661145X-RAY DIFFRACTION99.421
5.678-8.0090.302430.205896X-RAY DIFFRACTION99.8936
8.009-43.9940.185300.178506X-RAY DIFFRACTION99.2593

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