PDB-9fxy: Crystal Structure of Autotaxin (ENPP2) with Type IV Inhibitor

ID or keywords:

Entry

Database: PDB / ID: 9fxy

Title

Crystal Structure of Autotaxin (ENPP2) with Type IV Inhibitor

Components

Isoform 2 of Autotaxin

Keywords

HYDROLASE / Type VI / Inhibitor / Complex / Ectonucleotide Pyrophosphatase/Phosphodiesterase 2 / lysophospholipase D (lysoPLD) / lysophosphatidic acid (LPA)

Function / homology

Function and homology information

response to polycyclic arene / alkylglycerophosphoethanolamine phosphodiesterase / sphingolipid catabolic process / phospholipase D / phospholipid catabolic process / phosphatidylcholine catabolic process / phospholipase D activity / positive regulation of lamellipodium morphogenesis / phosphodiesterase I activity / phosphatidylcholine lysophospholipase activity ...
Similarity search - Function

Biological species

Rattus norvegicus (Norway rat)

Method

X-RAY DIFFRACTION /

SYNCHROTRON /

MOLECULAR REPLACEMENT / Resolution: 2 Å

Authors

Borza, R. / Joosten, R.P. / Perrakis, A.

Funding support

Netherlands, 1items

Citation

Journal: Bioorg.Med.Chem. / Year: 2025
Title: Design, Synthesis, and Biological Implications of Autotaxin inhibitors with a Three-Point lock binding mode.
Authors: Desroy, N. / Borza, R. / Heiermann, J. / Triballeau, N. / Joncour, A. / Bienvenu, N. / Hengeveld, W.J. / Springer, J. / Galien, R. / Joosten, R.P. / Perrakis, A. / Heckmann, B.

History

Deposition	Jul 2, 2024	Deposition site: PDBE / Processing site: PDBE
Revision 1.0	Apr 23, 2025	Provider: repository / Type: Initial release
Revision 1.1	Apr 30, 2025	Group: Database references / Category: citation Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title

Structure viewer	Molecule: MolmilJmol/JSmol

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Validation report

Summary document	9fxy_validation.pdf.gz	1.1 MB	Display	wwPDB validaton report
Full document	9fxy_full_validation.pdf.gz	1.1 MB	Display
Data in XML	9fxy_validation.xml.gz	39.5 KB	Display
Data in CIF	9fxy_validation.cif.gz	54.3 KB	Display
Arichive directory	https://data.pdbj.org/pub/pdb/validation_reports/fx/9fxy ftp://data.pdbj.org/pub/pdb/validation_reports/fx/9fxy	HTTPS FTP

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Related structure data

Related structure data	9ftnC 9fxuC 9fxwC C: citing same article (ref.)
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
Related items in Molecule of the Month	#50 - Feb 2004 Glycolytic Enzymes similarity (1) #190 - Oct 2015 Two-component Systems similarity (1)

Deposited unit

A: Isoform 2 of Autotaxin

hetero molecules

97.8 kDa, 1 polymers
Search similar-shape structures of this assembly by Omokage search (details)

1

Idetical with deposited unit
defined by author&software

Unit cell

Length a, b, c (Å)	53.603, 62.885, 64.594
Angle α, β, γ (deg.)	105.724, 96.546, 93.615
Int Tables number	1
Space group name H-M	P1

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Protein / Sugars , 2 types, 2 molecules A

#1: Protein

Isoform 2 of Autotaxin / Ectonucleotide pyrophosphatase/phosphodiesterase family member 2 / E-NPP 2 / Extracellular ...

Mass: 92875.422 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.)

Rattus norvegicus (Norway rat) / Gene: Enpp2, Atx, Npps2 / Production host:

Homo sapiens (human)
References: UniProt: Q64610, alkylglycerophosphoethanolamine phosphodiesterase, phospholipase D

#2: Polysaccharide

beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta- ...

Type: oligosaccharide / Mass: 586.542 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source

Descriptor	Type	Program
DManpb1-4DGlcpNAcb1-4DGlcpNAcb1-ROH	Glycam Condensed Sequence	GMML 1.0
WURCS=2.0/2,3,2/[a2122h-1b_1-5_2*NCC/3=O][a1122h-1b_1-5]/1-1-2/a4-b1_b4-c1	WURCS	PDB2Glycan 1.1.0
[][D-1-deoxy-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-Manp]{}}}	LINUCS	PDB-CARE

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Non-polymers , 8 types, 423 molecules

#3: Chemical	... ChemComp-SCN / THIOCYANATE ION Mass: 58.082 Da / Num. of mol.: 40 / Source method: obtained synthetically / Formula: CNS
#4: Chemical	ChemComp-ZN / ZINC ION Mass: 65.409 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Zn
#5: Chemical	ChemComp-CA / CALCIUM ION Mass: 40.078 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Ca
#6: Chemical	ChemComp-IOD / IODIDE ION Mass: 126.904 Da / Num. of mol.: 7 / Source method: obtained synthetically / Formula: I
#7: Chemical	ChemComp-A1IG1 / 3-(3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)-6-(1-(methylsulfonyl)piperidin-4-yl)imidazo[1,2-b]pyridazin-2-yl)propanenitrile / 3-[3-[[4-(4-fluorophenyl)-1,3-thiazol-2-yl]-methyl-amino]-6-(1-methylsulfonylpiperidin-4-yl)imidazo[1,2-b]pyridazin-2-yl]propanenitrile Mass: 539.648 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C₂₅H₂₆FN₇O₂S₂ / Feature type: SUBJECT OF INVESTIGATION
#8: Chemical	ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL Mass: 92.094 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C₃H₈O₃
#9: Chemical	ChemComp-PO4 / PHOSPHATE ION Mass: 94.971 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: PO₄
#10: Water	ChemComp-HOH / water Mass: 18.015 Da / Num. of mol.: 368 / Source method: isolated from a natural source / Formula: H₂O

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Details

Has ligand of interest	Y
Has protein modification	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: 2.29 Å³/Da / Density % sol: 46.4 %
Crystal grow	Temperature: 293 K / Method: vapor diffusion, hanging drop Details: ATX was incubated with each screened compound at a 1:10 (protein:compound) ratio for at least 30 minutes. Crystals were grown for at least 7 days in a 24-well optimization screen: 18 to 20% ...Details: ATX was incubated with each screened compound at a 1:10 (protein:compound) ratio for at least 30 minutes. Crystals were grown for at least 7 days in a 24-well optimization screen: 18 to 20% PEG 3350, 0.1 to 0.4 M NaSCN, and 0.1 to 0.4 M NH4I.

Crystal

Density Matthews: 2.29 Å³/Da / Density % sol: 46.4 %

Crystal grow

Temperature: 293 K / Method: vapor diffusion, hanging drop
Details: ATX was incubated with each screened compound at a 1:10 (protein:compound) ratio for at least 30 minutes. Crystals were grown for at least 7 days in a 24-well optimization screen: 18 to 20% ...

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Data collection

Diffraction	Mean temperature: 100 K / Serial crystal experiment: N
Diffraction source	Source: SYNCHROTRON / Site: ESRF / Beamline: MASSIF-1 / Wavelength: 0.965459 Å
Detector	Type: DECTRIS PILATUS3 2M / Detector: PIXEL / Date: May 6, 2021
Radiation	Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelength	Wavelength: 0.965459 Å / Relative weight: 1
Reflection	Resolution: 2→43.19 Å / Num. obs: 52110 / % possible obs: 96 % / Redundancy: 1.7 % / CC_1/2: 0.983 / R_merge(I) obs: 0.097 / R_pim(I) all: 0.097 / R_rim(I) all: 0.137 / Net I/σ(I): 5.5
Reflection shell	Resolution: 2→2.05 Å / Redundancy: 1.7 % / Num. unique obs: 3821 / CC_1/2: 0.588 / % possible all: 94.4

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Processing

Software

Name	Version	Classification
REFMAC	5.8.0419	refinement
Aimless	1.12.15	data scaling
MOLREP	11.7.03	phasing
Coot	0.9.8.92	model building
MolProbity	4.5.2	model building
XDS		data reduction
PDB-REDO		refinement

Refinement

Method to determine structure:

MOLECULAR REPLACEMENT / Resolution: 2→43.19 Å / Cor.coef. F_o:F_c: 0.958 / Cor.coef. F_o:F_c free: 0.94 / SU B: 11.11 / SU ML: 0.14 / Cross valid method: THROUGHOUT / ESU R: 0.199 / ESU R Free: 0.168
Details: Hydrogens have been added in their riding positions

	R_factor	Num. reflection	% reflection	Selection details
R_free	0.2175	2571	4.935 %	RANDOM
R_work	0.1709	49531	-	-
all	0.173	-	-	-
obs	-	52102	95.998 %	-

Solvent computation

Ion probe radii: 0.7 Å / Shrinkage radii: 0.7 Å / VDW probe radii: 1.1 Å / Solvent model: MASK BULK SOLVENT

Displacement parameters

B_iso mean: 31.226 Å²

	B_aniso -1	B_aniso -2	B_aniso -3
1-	-0.263 Å²	0.065 Å²	0.689 Å²
2-	-	-0.355 Å²	-0.166 Å²
3-	-	-	0.434 Å²

Refinement step

Cycle: LAST / Resolution: 2→43.19 Å

	Protein	Nucleic acid	Ligand	Solvent	Total
Num. atoms	6339	0	229	368	6936

Refine LS restraints

Refine-ID	Type	Dev ideal	Dev ideal target	Number
X-RAY DIFFRACTION	r_bond_refined_d	0.013	0.016	6727
X-RAY DIFFRACTION	r_bond_other_d	0.001	0.016	6009
X-RAY DIFFRACTION	r_angle_refined_deg	1.382	1.783	9066
X-RAY DIFFRACTION	r_angle_other_deg	0.484	1.567	13921
X-RAY DIFFRACTION	r_dihedral_angle_1_deg	9.823	5.283	831
X-RAY DIFFRACTION	r_dihedral_angle_2_deg	14.969	10	11
X-RAY DIFFRACTION	r_dihedral_angle_3_deg	14.076	10	1089
X-RAY DIFFRACTION	r_dihedral_angle_6_deg	16.526	10	314
X-RAY DIFFRACTION	r_chiral_restr	0.072	0.2	930
X-RAY DIFFRACTION	r_gen_planes_refined	0.006	0.02	7696
X-RAY DIFFRACTION	r_gen_planes_other	0.001	0.02	1557
X-RAY DIFFRACTION	r_nbd_refined	0.213	0.2	1432
X-RAY DIFFRACTION	r_symmetry_nbd_other	0.193	0.2	5828
X-RAY DIFFRACTION	r_nbtor_refined	0.185	0.2	3231
X-RAY DIFFRACTION	r_symmetry_nbtor_other	0.083	0.2	3412
X-RAY DIFFRACTION	r_xyhbond_nbd_refined	0.166	0.2	340
X-RAY DIFFRACTION	r_symmetry_xyhbond_nbd_other	0.028	0.2	2
X-RAY DIFFRACTION	r_metal_ion_refined	0.14	0.2	8
X-RAY DIFFRACTION	r_symmetry_nbd_refined	0.165	0.2	16
X-RAY DIFFRACTION	r_nbd_other	0.232	0.2	59
X-RAY DIFFRACTION	r_symmetry_xyhbond_nbd_refined	0.082	0.2	4
X-RAY DIFFRACTION	r_mcbond_it	5.636	1.804	3182
X-RAY DIFFRACTION	r_mcbond_other	5.096	1.78	3142
X-RAY DIFFRACTION	r_mcangle_it	6.298	3.181	3924
X-RAY DIFFRACTION	r_mcangle_other	6.297	3.182	3925
X-RAY DIFFRACTION	r_scbond_it	8.567	2.387	3545
X-RAY DIFFRACTION	r_scbond_other	8.568	2.387	3545
X-RAY DIFFRACTION	r_scangle_it	11.042	4.055	5142
X-RAY DIFFRACTION	r_scangle_other	11.031	4.056	5142
X-RAY DIFFRACTION	r_lrange_it	12.424	23.103	30048
X-RAY DIFFRACTION	r_lrange_other	12.431	23.03	29942

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	0.309	179	0.274	3634	X-RAY DIFFRACTION	94.4279
2.052-2.108	0.303	190	0.262	3459	X-RAY DIFFRACTION	93.6842
2.108-2.169	0.273	185	0.231	3465	X-RAY DIFFRACTION	95.375
2.169-2.235	0.273	170	0.222	3405	X-RAY DIFFRACTION	96.1797
2.235-2.309	0.247	180	0.197	3236	X-RAY DIFFRACTION	96.5517
2.309-2.389	0.235	181	0.188	3107	X-RAY DIFFRACTION	96.028
2.389-2.479	0.24	160	0.173	3074	X-RAY DIFFRACTION	96.25
2.479-2.58	0.234	154	0.165	2954	X-RAY DIFFRACTION	96.4618
2.58-2.694	0.263	135	0.163	2806	X-RAY DIFFRACTION	95.8605
2.694-2.825	0.224	128	0.147	2723	X-RAY DIFFRACTION	96.2525
2.825-2.978	0.196	127	0.141	2532	X-RAY DIFFRACTION	94.8626
2.978-3.157	0.176	133	0.13	2408	X-RAY DIFFRACTION	95.8145
3.157-3.374	0.175	126	0.132	2286	X-RAY DIFFRACTION	97.731
3.374-3.642	0.196	110	0.138	2137	X-RAY DIFFRACTION	96.9789
3.642-3.987	0.182	76	0.141	1999	X-RAY DIFFRACTION	97.3721
3.987-4.453	0.138	98	0.133	1784	X-RAY DIFFRACTION	96.8605
4.453-5.133	0.191	93	0.144	1558	X-RAY DIFFRACTION	97.2893
5.133-6.265	0.247	68	0.208	1324	X-RAY DIFFRACTION	96.1326
6.265-8.768	0.282	61	0.222	1043	X-RAY DIFFRACTION	98.0462
8.768-43.19	0.269	17	0.266	597	X-RAY DIFFRACTION	96.8454

Refinement TLS params.

Method: refined / Origin x: 0.6063 Å / Origin y: -0.0992 Å / Origin z: 1.0771 Å

	11	12	13	21	22	23	31	32	33
T	0.0643 Å²	-0.0623 Å²	-0.0312 Å²	-	0.0609 Å²	0.0297 Å²	-	-	0.0155 Å²
L	0.4458 °²	0.0856 °²	0.1424 °²	-	0.6284 °²	0.1155 °²	-	-	0.7726 °²
S	0.0066 Å °	-0.0022 Å °	-0.0057 Å °	0.0088 Å °	0.0085 Å °	-0.0176 Å °	0.0061 Å °	0.0065 Å °	-0.0151 Å °

Refinement TLS group

Selection: ALL

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