PDB-8jyg: Crystal structure of Human HPSE1 in complex with inhibitor

ID or keywords:

Entry

Database: PDB / ID: 8jyg

Title

Crystal structure of Human HPSE1 in complex with inhibitor

Components

Heparanase
Heparanase 50 kDa subunit

Keywords

HYDROLASE/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 ...
Similarity search - Function

Biological species

Homo sapiens (human)

Method

X-RAY DIFFRACTION /

SYNCHROTRON /

MOLECULAR REPLACEMENT / Resolution: 2 Å

Authors

Mima, M. / Fujimoto, N. / Imai, Y.

Funding support

1items

Citation

Journal: Bioorg.Med.Chem. / Year: 2023
Title: Structure-based lead optimization to improve potency and selectivity of a novel tetrahydroimidazo[1,2-a]pyridine-5-carboxylic acid series of heparanase-1 inhibitor.
Authors: Imai, Y. / Suzuki, R. / Wakasugi, D. / Matsuda, D. / Tanaka-Yamamoto, N. / Ohki, Y. / Mima, M. / Endo, M. / Tabata, R. / Matsuzawa, H. / Hasegawa, Y. / Kato, S. / Sugisaki, M. / Miyagawa, H. ...

History

Deposition	Jul 3, 2023	Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0	Sep 20, 2023	Provider: repository / Type: Initial release

Structure viewer	Molecule: MolmilJmol/JSmol

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Download

PDBx/mmCIF format	8jyg.cif.gz	120.5 KB	Display	PDBx/mmCIF format
PDB format	pdb8jyg.ent.gz	85.9 KB	Display	PDB format
PDBx/mmJSON format	8jyg.json.gz		Tree view	PDBx/mmJSON format
Others	Other downloads

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Validation report

Summary document	8jyg_validation.pdf.gz	1.2 MB	Display	wwPDB validaton report
Full document	8jyg_full_validation.pdf.gz	1.2 MB	Display
Data in XML	8jyg_validation.xml.gz	21.8 KB	Display
Data in CIF	8jyg_validation.cif.gz	31.1 KB	Display
Arichive directory	https://data.pdbj.org/pub/pdb/validation_reports/jy/8jyg ftp://data.pdbj.org/pub/pdb/validation_reports/jy/8jyg	HTTPS FTP

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Related structure data

Related structure data	5e8mS S: Starting model for refinement
Similar structure data	Similarity search - Function & homologyF&H Search Similarity search - FunctionF&H Search Similarity search - HomologyF&H Search

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Links

PDB pages	PDBj / wwPDB / NCBI

Deposited unit

A: Heparanase 50 kDa subunit

B: Heparanase

hetero molecules

54.1 kDa, 2 polymers
Search similar-shape structures of this assembly by Omokage search (details)

1

Idetical with deposited unit
defined by author&software
Evidence: gel filtration

Unit cell

Length a, b, c (Å)	44.380, 71.049, 78.280
Angle α, β, γ (deg.)	90.000, 98.090, 90.000
Int Tables number	4
Space group name H-M	P12₁1

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Protein , 2 types, 2 molecules AB

#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 / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: Q9Y251, heparanase
#2: Protein	Heparanase / Endo-glucoronidase / Heparanase-1 / Hpa1 Mass: 8415.670 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, heparanase

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Sugars , 1 types, 2 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.: 2 / Source method: obtained synthetically / Formula: C₈H₁₅NO₆ / Feature type: SUBJECT OF INVESTIGATION

Identifier	Type	Program
DGlcpNAcb	CONDENSED IUPAC CARBOHYDRATE SYMBOL	GMML 1.0
N-acetyl-b-D-glucopyranosamine	COMMON NAME	GMML 1.0
b-D-GlcpNAc	IUPAC CARBOHYDRATE SYMBOL	PDB-CARE 1.0
GlcNAc	SNFG CARBOHYDRATE SYMBOL	GMML 1.0

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Non-polymers , 3 types, 231 molecules

#3: Chemical	ChemComp-V8R / (5~{S},6~{R},7~{S},8~{S})-6,7,8-tris(oxidanyl)-2-[2-(3-phenoxyphenyl)ethyl]-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-5-carboxylic acid Mass: 410.420 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C₂₂H₂₂N₂O₆ / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical	... ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL Mass: 62.068 Da / Num. of mol.: 22 / Source method: obtained synthetically / Formula: C₂H₆O₂
#6: Water	ChemComp-HOH / water Mass: 18.015 Da / Num. of mol.: 208 / Source method: isolated from a natural source / Formula: H₂O

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Details

Has ligand of interest	Y

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Experiment

Experiment	Method: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

Crystal	Density Matthews: 2.36 Å³/Da / Density % sol: 47.77 %
Crystal grow	Temperature: 293 K / Method: vapor diffusion / pH: 5.5 Details: 25% w/v Polyethylene glycol 3,350, 100 mM BIS-TRIS pH 5.5

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Data collection

Diffraction	Mean temperature: 100 K / Serial crystal experiment: N
Diffraction source	Source: SYNCHROTRON / Site: SLS / Beamline: X10SA / Wavelength: 1.00003 Å
Detector	Type: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Dec 10, 2018
Radiation	Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelength	Wavelength: 1.00003 Å / Relative weight: 1
Reflection	Resolution: 2→77.5 Å / Num. obs: 32623 / % possible obs: 99.8 % / Redundancy: 5.3 % / CC_1/2: 0.993 / Net I/σ(I): 7.5
Reflection shell	Resolution: 2→2.05 Å / Num. unique obs: 2388 / CC_1/2: 0.79

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Processing

Software

Name	Version	Classification
REFMAC	5.8.0267	refinement
iMOSFLM		data reduction
Aimless		data scaling
MOLREP		phasing

Refinement

Method to determine structure:

MOLECULAR REPLACEMENT
Starting model: 5E8M

5e8m

Resolution: 2→43.977 Å / Cor.coef. F_o:F_c: 0.966 / Cor.coef. F_o:F_c free: 0.951 / SU B: 4.914 / SU ML: 0.128 / Cross valid method: THROUGHOUT / ESU R: 0.174 / ESU R Free: 0.153
Details: Hydrogens have been added in their riding positions

	R_factor	Num. reflection	% reflection
R_free	0.2092	1600	4.907 %
R_work	0.1656	31005	-
all	0.168	-	-
obs	-	32605	99.807 %

Solvent computation

Ion probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK BULK SOLVENT

Displacement parameters

B_iso mean: 32.783 Å²

	B_aniso -1	B_aniso -2	B_aniso -3
1-	-0.678 Å²	0 Å²	1.313 Å²
2-	-	-3.109 Å²	-0 Å²
3-	-	-	3.282 Å²

Refinement step

Cycle: LAST / Resolution: 2→43.977 Å

	Protein	Nucleic acid	Ligand	Solvent	Total
Num. atoms	3644	0	146	208	3998

Refine LS restraints

Refine-ID	Type	Dev ideal	Dev ideal target	Number
X-RAY DIFFRACTION	r_bond_refined_d	0.009	0.013	3862
X-RAY DIFFRACTION	r_bond_other_d	0.001	0.015	3750
X-RAY DIFFRACTION	r_angle_refined_deg	1.582	1.675	5193
X-RAY DIFFRACTION	r_angle_other_deg	1.273	1.595	8628
X-RAY DIFFRACTION	r_dihedral_angle_1_deg	7.204	5	458
X-RAY DIFFRACTION	r_dihedral_angle_2_deg	33.751	21.823	181
X-RAY DIFFRACTION	r_dihedral_angle_3_deg	14.579	15	643
X-RAY DIFFRACTION	r_dihedral_angle_4_deg	21.087	15	22
X-RAY DIFFRACTION	r_chiral_restr	0.07	0.2	478
X-RAY DIFFRACTION	r_gen_planes_refined	0.008	0.02	4231
X-RAY DIFFRACTION	r_gen_planes_other	0.001	0.02	890
X-RAY DIFFRACTION	r_nbd_refined	0.201	0.2	790
X-RAY DIFFRACTION	r_symmetry_nbd_other	0.184	0.2	3614
X-RAY DIFFRACTION	r_nbtor_refined	0.168	0.2	1860
X-RAY DIFFRACTION	r_symmetry_nbtor_other	0.077	0.2	1856
X-RAY DIFFRACTION	r_xyhbond_nbd_refined	0.17	0.2	206
X-RAY DIFFRACTION	r_symmetry_xyhbond_nbd_other	0.017	0.2	2
X-RAY DIFFRACTION	r_symmetry_nbd_refined	0.177	0.2	22
X-RAY DIFFRACTION	r_nbd_other	0.217	0.2	77
X-RAY DIFFRACTION	r_symmetry_xyhbond_nbd_refined	0.234	0.2	11
X-RAY DIFFRACTION	r_mcbond_it	2.593	3.181	1838
X-RAY DIFFRACTION	r_mcbond_other	2.57	3.177	1837
X-RAY DIFFRACTION	r_mcangle_it	3.935	4.757	2294
X-RAY DIFFRACTION	r_mcangle_other	3.939	4.761	2295
X-RAY DIFFRACTION	r_scbond_it	3.2	3.605	2024
X-RAY DIFFRACTION	r_scbond_other	3.199	3.606	2025
X-RAY DIFFRACTION	r_scangle_it	4.948	5.221	2899
X-RAY DIFFRACTION	r_scangle_other	4.948	5.222	2900
X-RAY DIFFRACTION	r_lrange_it	8.651	61.462	17654
X-RAY DIFFRACTION	r_lrange_other	8.651	61.448	17643

LS refinement shell

Resolution (Å)	R_factor R_free	Num. reflection R_free	R_factor R_work	Num. reflection R_work	Refine-ID	% reflection obs (%)
2-2.052	0.273	134	0.254	2254	X-RAY DIFFRACTION	99.7911
2.052-2.108	0.251	115	0.234	2233	X-RAY DIFFRACTION	99.6604
2.108-2.169	0.229	103	0.225	2144	X-RAY DIFFRACTION	99.6011
2.169-2.236	0.258	110	0.208	2109	X-RAY DIFFRACTION	99.7303
2.236-2.309	0.239	115	0.196	2012	X-RAY DIFFRACTION	99.953
2.309-2.39	0.228	97	0.181	1989	X-RAY DIFFRACTION	99.9521
2.39-2.48	0.251	101	0.183	1930	X-RAY DIFFRACTION	99.8525
2.48-2.581	0.215	105	0.166	1802	X-RAY DIFFRACTION	99.8952
2.581-2.696	0.23	85	0.16	1750	X-RAY DIFFRACTION	99.4041
2.696-2.828	0.25	83	0.161	1693	X-RAY DIFFRACTION	99.7753
2.828-2.98	0.229	81	0.159	1607	X-RAY DIFFRACTION	99.7047
2.98-3.161	0.205	85	0.161	1510	X-RAY DIFFRACTION	100
3.161-3.379	0.235	72	0.168	1424	X-RAY DIFFRACTION	99.9332
3.379-3.649	0.172	70	0.146	1332	X-RAY DIFFRACTION	99.8576
3.649-3.996	0.201	61	0.144	1228	X-RAY DIFFRACTION	99.9225
3.996-4.466	0.125	51	0.124	1117	X-RAY DIFFRACTION	100
4.466-5.154	0.147	41	0.123	986	X-RAY DIFFRACTION	99.9027
5.154-6.306	0.204	35	0.168	861	X-RAY DIFFRACTION	100
6.306-8.888	0.212	38	0.155	648	X-RAY DIFFRACTION	99.8544
8.888-43.977	0.157	18	0.151	376	X-RAY DIFFRACTION	99.7468

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