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- PDB-8b0c: Crystal structure of human heparanase in complex with covalent in... -

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Basic information

Entry
Database: PDB / ID: 8b0c
TitleCrystal structure of human heparanase in complex with covalent inhibitor VB158
Components
  • Heparanase 50 kDa subunit
  • Heparanase 8 kDa subunit
KeywordsHYDROLASE / Heparanase
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-OV3 / Heparanase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.1 Å
AuthorsArmstrong, Z. / Davies, G.
Funding support United Kingdom, 1items
OrganizationGrant numberCountry
Biotechnology and Biological Sciences Research Council (BBSRC)BB/R001162/1 United Kingdom
CitationJournal: Chemmedchem / Year: 2023
Title: 4-O-Substituted Glucuronic Cyclophellitols are Selective Mechanism-Based Heparanase Inhibitors.
Authors: Borlandelli, V. / Armstrong, Z. / Nin-Hill, A. / Codee, J.D.C. / Raich, L. / Artola, M. / Rovira, C. / Davies, G.J. / Overkleeft, H.S.
History
DepositionSep 7, 2022Deposition site: PDBE / Processing site: PDBE
Revision 1.0Dec 28, 2022Provider: repository / Type: Initial release
Revision 1.1Feb 1, 2023Group: Database references / Category: citation / citation_author
Item: _citation.page_first / _citation.page_last ..._citation.page_first / _citation.page_last / _citation_author.identifier_ORCID / _citation_author.name
Revision 1.2Mar 1, 2023Group: Database references / Category: citation / Item: _citation.journal_volume / _citation.year
Revision 1.3Feb 7, 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
AAA: Heparanase 50 kDa subunit
BBB: Heparanase 8 kDa subunit
hetero molecules


Theoretical massNumber of molelcules
Total (without water)52,6036
Polymers51,6082
Non-polymers9954
Water1,22568
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area9080 Å2
ΔGint-47 kcal/mol
Surface area18900 Å2
MethodPISA
Unit cell
Length a, b, c (Å)45.976, 71.441, 78.261
Angle α, β, γ (deg.)90.000, 95.450, 90.000
Int Tables number4
Space group name H-MP1211

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Components

#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
#3: 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.: 3
Source method: isolated from a genetically manipulated source
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
#4: Chemical ChemComp-OV3 / (1~{S},2~{R},3~{R},4~{S},6~{S})-3,4,6-tris(oxidanyl)-2-[2-[2,2,2-tris(fluoranyl)ethanoylamino]ethoxy]cyclohexane-1-carboxylic acid


Mass: 331.242 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C11H16F3NO7 / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 68 / Source method: isolated from a natural source / Formula: H2O
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: 2.49 Å3/Da / Density % sol: 50.51 %
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: 0.9762 Å
DetectorType: DECTRIS EIGER2 X 16M / Detector: PIXEL / Date: Jul 4, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9762 Å / Relative weight: 1
ReflectionResolution: 2.1→52.71 Å / Num. obs: 29584 / % possible obs: 100 % / Redundancy: 5.7 % / CC1/2: 0.998 / Net I/σ(I): 8.3
Reflection shellResolution: 2.1→2.16 Å / Mean I/σ(I) obs: 0.8 / Num. unique obs: 2411 / CC1/2: 0.592

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Processing

Software
NameVersionClassification
REFMAC5.8.0258refinement
DIALSdata reduction
DIALSdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5e8m

5e8m


Resolution: 2.1→52.71 Å / Cor.coef. Fo:Fc: 0.961 / Cor.coef. Fo:Fc free: 0.93 / WRfactor Rfree: 0.236 / WRfactor Rwork: 0.182 / SU B: 7.793 / SU ML: 0.194 / Average fsc free: 0.8387 / Average fsc work: 0.8667 / Cross valid method: FREE R-VALUE / ESU R: 0.231 / ESU R Free: 0.205
Details: Hydrogens have been added in their riding positions
RfactorNum. reflection% reflection
Rfree0.2621 1439 4.867 %
Rwork0.2015 28129 -
all0.204 --
obs-29568 99.929 %
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: 47.328 Å2
Baniso -1Baniso -2Baniso -3
1-2.149 Å2-0 Å22.116 Å2
2---2.335 Å2-0 Å2
3----0.214 Å2
Refinement stepCycle: LAST / Resolution: 2.1→52.71 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3610 0 64 68 3742
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0090.0133783
X-RAY DIFFRACTIONr_bond_other_d0.0010.0173529
X-RAY DIFFRACTIONr_angle_refined_deg1.6681.6575143
X-RAY DIFFRACTIONr_angle_other_deg1.2621.598190
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.725458
X-RAY DIFFRACTIONr_dihedral_angle_2_deg33.84221.833180
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.47115628
X-RAY DIFFRACTIONr_dihedral_angle_4_deg13.1761521
X-RAY DIFFRACTIONr_chiral_restr0.0690.2486
X-RAY DIFFRACTIONr_gen_planes_refined0.0080.024175
X-RAY DIFFRACTIONr_gen_planes_other0.0020.02806
X-RAY DIFFRACTIONr_nbd_refined0.2170.2727
X-RAY DIFFRACTIONr_symmetry_nbd_other0.1810.23259
X-RAY DIFFRACTIONr_nbtor_refined0.1710.21798
X-RAY DIFFRACTIONr_symmetry_nbtor_other0.0790.21749
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1420.2119
X-RAY DIFFRACTIONr_symmetry_nbd_refined0.2330.26
X-RAY DIFFRACTIONr_nbd_other0.2810.231
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_refined0.090.23
X-RAY DIFFRACTIONr_mcbond_it4.0774.8881835
X-RAY DIFFRACTIONr_mcbond_other4.0754.8881834
X-RAY DIFFRACTIONr_mcangle_it5.5767.3252292
X-RAY DIFFRACTIONr_mcangle_other5.5767.3252293
X-RAY DIFFRACTIONr_scbond_it4.3925.2711948
X-RAY DIFFRACTIONr_scbond_other4.3945.271945
X-RAY DIFFRACTIONr_scangle_it6.3877.7482851
X-RAY DIFFRACTIONr_scangle_other6.3887.7482850
X-RAY DIFFRACTIONr_lrange_it7.98456.4594050
X-RAY DIFFRACTIONr_lrange_other7.98756.4954043
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.1-2.1540.2811000.3012052X-RAY DIFFRACTION99.8145
2.154-2.2130.32970.2842024X-RAY DIFFRACTION100
2.213-2.2780.3041120.2641938X-RAY DIFFRACTION100
2.278-2.3480.3221240.2641906X-RAY DIFFRACTION99.9508
2.348-2.4240.2691150.2471843X-RAY DIFFRACTION99.898
2.424-2.5090.293940.2381759X-RAY DIFFRACTION100
2.509-2.6040.306920.2381713X-RAY DIFFRACTION100
2.604-2.710.366820.2181687X-RAY DIFFRACTION100
2.71-2.8310.288770.2021583X-RAY DIFFRACTION100
2.831-2.9690.326740.2151534X-RAY DIFFRACTION100
2.969-3.1290.311660.2151476X-RAY DIFFRACTION99.9352
3.129-3.3180.317590.2251374X-RAY DIFFRACTION100
3.318-3.5470.259620.2191322X-RAY DIFFRACTION100
3.547-3.8310.26570.2111195X-RAY DIFFRACTION100
3.831-4.1950.215540.1831123X-RAY DIFFRACTION100
4.195-4.6890.181410.1451011X-RAY DIFFRACTION99.8102
4.689-5.4110.193260.142908X-RAY DIFFRACTION100
5.411-6.6190.269540.171759X-RAY DIFFRACTION100
6.619-9.3270.238320.162583X-RAY DIFFRACTION100
9.327-52.710.192210.168339X-RAY DIFFRACTION99.4475

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