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- PDB-7yi7: Crystal structure of Human HPSE1 in complex with inhibitor -

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Basic information

Entry
Database: PDB / ID: 7yi7
TitleCrystal structure of Human HPSE1 in complex with inhibitor
Components
  • Heparanase 50 kDa subunit
  • Heparanase 8 kDa subunit
KeywordsHYDROLASE/INHIBITOR / Endo-glucoronidase / Heparanase-1 / HEP / HPA / HPA1 / HPR1 / HPSE1 / HSE1 / HYDROLASE / HYDROLASE-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-IUV / Heparanase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.8 Å
AuthorsMima, M. / Fujimoto, N. / Imai, Y.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2022
Title: Lead identification of novel tetrahydroimidazo[1,2-a]pyridine-5-carboxylic acid derivative as a potent heparanase-1 inhibitor.
Authors: Imai, Y. / Wakasugi, D. / Suzuki, R. / Kato, S. / Sugisaki, M. / Mima, M. / Miyagawa, H. / Endo, M. / Fujimoto, N. / Fukunaga, T. / Kato, S. / Kuroda, S. / Takahashi, T. / Kakinuma, H.
History
DepositionJul 15, 2022Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Dec 7, 2022Provider: repository / Type: Initial release
Revision 1.1Nov 29, 2023Group: 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

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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)52,1243
Polymers51,7382
Non-polymers3861
Water23413
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area8270 Å2
ΔGint-57 kcal/mol
Surface area18760 Å2
MethodPISA
Unit cell
Length a, b, c (Å)49.974, 60.090, 78.423
Angle α, β, γ (deg.)90.00, 89.16, 90.00
Int Tables number4
Space group name H-MP1211

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Components

#1: Protein Heparanase 50 kDa subunit


Mass: 43464.074 Da / Num. of mol.: 1 / Mutation: K307R
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: HPSE, HEP, HPA, HPA1, HPR1, HPSE1, HSE1 / Plasmid: pIEx4 / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: Q9Y251, heparanase
#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 / Plasmid: pIEx4 / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: Q9Y251, heparanase
#3: Chemical ChemComp-IUV / (5~{S},6~{R},7~{S},8~{S})-6,7,8-tris(oxidanyl)-2-[2-[4-(trifluoromethyl)phenyl]ethyl]-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-5-carboxylic acid


Mass: 386.322 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C17H17F3N2O5 / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 13 / 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: 2.28 Å3/Da / Density % sol: 45.95 %
Crystal growTemperature: 293 K / Method: vapor diffusion / pH: 4
Details: 12% w/v Polyethylene glycol 3,350, 100 mM Sodium malonate pH 4.0

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU MICROMAX-007 HF / Wavelength: 1.54184 Å
DetectorType: DECTRIS PILATUS 200K / Detector: PIXEL / Date: Oct 4, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54184 Å / Relative weight: 1
ReflectionResolution: 2.8→21.73 Å / Num. obs: 11532 / % possible obs: 99.4 % / Redundancy: 5.1 % / CC1/2: 0.983 / Net I/σ(I): 6.3
Reflection shellResolution: 2.8→2.95 Å / Num. unique obs: 1661 / CC1/2: 0.722

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Processing

Software
NameVersionClassification
REFMAC5.8.0189refinement
CrysalisProdata reduction
CrysalisProdata scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5E8M

5e8m


Resolution: 2.8→21.73 Å / Cor.coef. Fo:Fc: 0.944 / Cor.coef. Fo:Fc free: 0.897 / SU B: 30.68 / SU ML: 0.52 / Cross valid method: THROUGHOUT / ESU R Free: 0.467 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.28125 621 5.4 %RANDOM
Rwork0.21259 ---
obs0.2163 10902 99.21 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 58.406 Å2
Baniso -1Baniso -2Baniso -3
1--2.68 Å20 Å2-4.86 Å2
2--8.37 Å20 Å2
3----5.83 Å2
Refinement stepCycle: 1 / Resolution: 2.8→21.73 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3643 0 27 13 3683
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0110.0193761
X-RAY DIFFRACTIONr_bond_other_d0.0010.023548
X-RAY DIFFRACTIONr_angle_refined_deg1.4831.9835095
X-RAY DIFFRACTIONr_angle_other_deg0.79538229
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.3575457
X-RAY DIFFRACTIONr_dihedral_angle_2_deg37.86523.459159
X-RAY DIFFRACTIONr_dihedral_angle_3_deg17.24815647
X-RAY DIFFRACTIONr_dihedral_angle_4_deg16.3891522
X-RAY DIFFRACTIONr_chiral_restr0.0770.2567
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.0214101
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02790
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it3.9635.721834
X-RAY DIFFRACTIONr_mcbond_other3.9615.7191833
X-RAY DIFFRACTIONr_mcangle_it6.4248.5642289
X-RAY DIFFRACTIONr_mcangle_other6.4238.5662290
X-RAY DIFFRACTIONr_scbond_it3.5886.0661927
X-RAY DIFFRACTIONr_scbond_other3.5886.0621924
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other6.0738.952805
X-RAY DIFFRACTIONr_long_range_B_refined11.75415124
X-RAY DIFFRACTIONr_long_range_B_other11.75415124
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.8→2.873 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.39 37 -
Rwork0.37 795 -
obs--99.76 %

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