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

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Basic information

Entry
Database: PDB / ID: 8bac
TitleCrystal structure of human heparanase in complex with competitive inhibitor GD05
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-SJ5 / Heparanase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.05 Å
AuthorsArmstrong, Z. / Davies, G.J.
Funding support United Kingdom, 1items
OrganizationGrant numberCountry
Biotechnology and Biological Sciences Research Council (BBSRC)Ken murray professorship United Kingdom
CitationJournal: Chembiochem / Year: 2023
Title: Synthesis of Uronic Acid 1-Azasugars as Putative Inhibitors of alpha-Iduronidase, beta-Glucuronidase and Heparanase.
Authors: Doherty, G.G. / Ler, G.J.M. / Wimmer, N. / Bernhardt, P.V. / Ashmus, R.A. / Vocadlo, D.J. / Armstrong, Z. / Davies, G.J. / Maccarana, M. / Li, J.P. / Kayal, Y. / Ferro, V.
History
DepositionOct 11, 2022Deposition site: PDBE / Processing site: PDBE
Revision 1.0Mar 1, 2023Provider: repository / Type: Initial release
Revision 1.1Feb 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)52,6726
Polymers52,0072
Non-polymers6664
Water1,69394
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area8920 Å2
ΔGint-49 kcal/mol
Surface area18900 Å2
MethodPISA
Unit cell
Length a, b, c (Å)44.838, 71.188, 78.628
Angle α, β, γ (deg.)90.000, 98.375, 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: 43733.324 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Details: Heparanase 50 kDa subunit / 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, 2 molecules

#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.: 2 / 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

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


Mass: 62.068 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6O2
#5: Chemical ChemComp-SJ5 / (3S,4R,5R)-4,5-dihydroxypiperidine-3-carboxylic acid


Mass: 161.156 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C6H11NO4 / Feature type: SUBJECT OF INVESTIGATION
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 94 / 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: 2.39 Å3/Da / Density % sol: 48.47 %
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: 0.976254 Å
DetectorType: DECTRIS EIGER2 XE 16M / Detector: PIXEL / Date: Dec 16, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.976254 Å / Relative weight: 1
ReflectionResolution: 2.05→37.677 Å / Num. obs: 30692 / % possible obs: 99.6 % / Redundancy: 6.7 % / CC1/2: 0.993 / Net I/σ(I): 6.2
Reflection shellResolution: 2.05→2.11 Å / Num. unique obs: 2345 / CC1/2: 0.672

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Processing

Software
NameVersionClassification
REFMAC5.8.0258refinement
xia2data reduction
xia2data scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 7PRT

7prt


Resolution: 2.05→37.677 Å / Cor.coef. Fo:Fc: 0.946 / Cor.coef. Fo:Fc free: 0.921 / WRfactor Rfree: 0.264 / WRfactor Rwork: 0.221 / SU B: 8.489 / SU ML: 0.214 / Average fsc free: 0.7967 / Average fsc work: 0.8169 / Cross valid method: FREE R-VALUE / ESU R: 0.241 / ESU R Free: 0.2
Details: Hydrogens have been added in their riding positions
RfactorNum. reflection% reflection
Rfree0.2674 1488 4.851 %
Rwork0.2235 29186 -
all0.226 --
obs-30674 99.549 %
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: 45.913 Å2
Baniso -1Baniso -2Baniso -3
1-2.055 Å2-0 Å24.443 Å2
2---5.089 Å2-0 Å2
3---1.655 Å2
Refinement stepCycle: LAST / Resolution: 2.05→37.677 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3627 0 43 94 3764
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0070.0133760
X-RAY DIFFRACTIONr_bond_other_d0.0030.0173540
X-RAY DIFFRACTIONr_angle_refined_deg1.5011.6525098
X-RAY DIFFRACTIONr_angle_other_deg1.2611.5868214
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.4085457
X-RAY DIFFRACTIONr_dihedral_angle_2_deg33.53422.09177
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.24115637
X-RAY DIFFRACTIONr_dihedral_angle_4_deg14.2521520
X-RAY DIFFRACTIONr_chiral_restr0.0650.2476
X-RAY DIFFRACTIONr_chiral_restr_other0.4060.21
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.024143
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02801
X-RAY DIFFRACTIONr_nbd_refined0.2050.2774
X-RAY DIFFRACTIONr_symmetry_nbd_other0.1950.23297
X-RAY DIFFRACTIONr_nbtor_refined0.1690.21823
X-RAY DIFFRACTIONr_symmetry_nbtor_other0.0820.21563
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1880.2143
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_other0.1130.22
X-RAY DIFFRACTIONr_symmetry_nbd_refined0.2240.29
X-RAY DIFFRACTIONr_nbd_other0.1850.224
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_refined0.2520.22
X-RAY DIFFRACTIONr_xyhbond_nbd_other0.0570.21
X-RAY DIFFRACTIONr_mcbond_it3.0924.7411834
X-RAY DIFFRACTIONr_mcbond_other3.094.741833
X-RAY DIFFRACTIONr_mcangle_it4.427.0992289
X-RAY DIFFRACTIONr_mcangle_other4.4197.1012290
X-RAY DIFFRACTIONr_scbond_it3.215.1041926
X-RAY DIFFRACTIONr_scbond_other3.2115.0971923
X-RAY DIFFRACTIONr_scangle_it4.9317.5122809
X-RAY DIFFRACTIONr_scangle_other4.9327.512808
X-RAY DIFFRACTIONr_lrange_it6.66255.6344154
X-RAY DIFFRACTIONr_lrange_other6.65855.6494149
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.05-2.1030.4211150.3422117X-RAY DIFFRACTION99.2
2.103-2.1610.321870.3052118X-RAY DIFFRACTION99.2796
2.161-2.2230.272830.2842050X-RAY DIFFRACTION99.4869
2.223-2.2920.2891140.2751950X-RAY DIFFRACTION99.5178
2.292-2.3670.331850.2781933X-RAY DIFFRACTION99.556
2.367-2.450.3061000.2541842X-RAY DIFFRACTION99.4368
2.45-2.5420.2911050.2431799X-RAY DIFFRACTION99.6859
2.542-2.6460.358800.2461727X-RAY DIFFRACTION99.2857
2.646-2.7640.344770.2411644X-RAY DIFFRACTION99.7103
2.764-2.8980.29910.231581X-RAY DIFFRACTION99.8209
2.898-3.0550.273690.221519X-RAY DIFFRACTION99.7487
3.055-3.240.295770.221445X-RAY DIFFRACTION99.7379
3.24-3.4630.254680.2311355X-RAY DIFFRACTION99.9298
3.463-3.740.274760.2271243X-RAY DIFFRACTION99.9242
3.74-4.0960.201590.1921157X-RAY DIFFRACTION100
4.096-4.5780.227590.1751028X-RAY DIFFRACTION99.6334
4.578-5.2830.234530.182936X-RAY DIFFRACTION99.7982
5.283-6.4630.318450.218784X-RAY DIFFRACTION99.6394
6.463-9.1080.192280.178615X-RAY DIFFRACTION99.2284
9.108-37.6770.131170.176343X-RAY DIFFRACTION96.7742

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