PDB-9ftn: Crystal Structure of Autotaxin (ENPP2) with Type VI Inhibitor, a ...

ID or keywords:

Entry

Database: PDB / ID: 9ftn

Title

Crystal Structure of Autotaxin (ENPP2) with Type VI Inhibitor, a Novel Class of Inhibitors with Three-Point Lock Binding Mode

Components

Isoform 2 of Ectonucleotide pyrophosphatase/phosphodiesterase family member 2

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: 2.9 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	Jun 25, 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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PDBx/mmCIF format	9ftn.cif.gz	821.2 KB	Display	PDBx/mmCIF format
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Validation report

Summary document	9ftn_validation.pdf.gz	1.8 MB	Display	wwPDB validaton report
Full document	9ftn_full_validation.pdf.gz	1.8 MB	Display
Data in XML	9ftn_validation.xml.gz	34.2 KB	Display
Data in CIF	9ftn_validation.cif.gz	45.3 KB	Display
Arichive directory	https://data.pdbj.org/pub/pdb/validation_reports/ft/9ftn ftp://data.pdbj.org/pub/pdb/validation_reports/ft/9ftn	HTTPS FTP

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Related structure data

Related structure data	9fxuC 9fxwC 9fxyC 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 Ectonucleotide pyrophosphatase/phosphodiesterase family member 2

hetero molecules

95.2 kDa, 1 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)	53.935, 63.558, 70.599
Angle α, β, γ (deg.)	98.991, 105.207, 99.647
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 Ectonucleotide pyrophosphatase/phosphodiesterase family member 2 / E-NPP 2 / Autotaxin / Extracellular lysophospholipase D / LysoPLD

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

#2: Polysaccharide

alpha-D-mannopyranose-(1-3)-[alpha-D-mannopyranose-(1-6)]beta-D-mannopyranose-(1-4)-2-acetamido-2- ...

Type: oligosaccharide / Mass: 910.823 Da / Num. of mol.: 1 / Source method: isolated from a natural source

Descriptor	Type	Program
DManpa1-3[DManpa1-6]DManpb1-4DGlcpNAcb1-4DGlcpNAcb1-ROH	Glycam Condensed Sequence	GMML 1.0
WURCS=2.0/3,5,4/[a2122h-1b_1-5_2*NCC/3=O][a1122h-1b_1-5][a1122h-1a_1-5]/1-1-2-3-3/a4-b1_b4-c1_c3-d1_c6-e1	WURCS	PDB2Glycan 1.1.0
[][D-1-deoxy-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-Manp]{[(3+1)][a-D-Manp]{}[(6+1)][a-D-Manp]{}}}}	LINUCS	PDB-CARE

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Non-polymers , 6 types, 140 molecules

#3: Chemical	ChemComp-ZN / ZINC ION Mass: 65.409 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Zn
#4: Chemical	ChemComp-CA / CALCIUM ION Mass: 40.078 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Ca
#5: Chemical	ChemComp-IOD / IODIDE ION Mass: 126.904 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: I
#6: Chemical	ChemComp-A1IG5 / 3-(3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)-6-(1-(methylsulfonyl)piperidin-4-yl)imidazo[1,2-b]pyridazin-2-yl)-N-(2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)propenamide / 3-[3-[[4-(4-fluorophenyl)-1,3-thiazol-2-yl]-methyl-amino]-6-(1-methylsulfonylpiperidin-4-yl)imidazo[1,2-b]pyridazin-2-yl]-N-(2-oxidanylidene-3H-1,3-benzoxazol-6-yl)propanamide Mass: 690.768 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C₃₂H₃₁FN₈O₅S₂ / Feature type: SUBJECT OF INVESTIGATION
#7: Chemical	ChemComp-SCN / THIOCYANATE ION Mass: 58.082 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: CNS
#8: Water	ChemComp-HOH / water Mass: 18.015 Da / Num. of mol.: 127 / 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: 2.21 Å³/Da / Density % sol: 44 %
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: 2.21 Å³/Da / Density % sol: 44 %

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: 2.9→47.78 Å / Num. obs: 18732 / % possible obs: 96.8 % / Redundancy: 1.7 % / CC_1/2: 0.965 / R_merge(I) obs: 0.13 / R_pim(I) all: 0.13 / R_rim(I) all: 0.184 / Net I/σ(I): 3.1
Reflection shell	Resolution: 2.9→3.08 Å / Redundancy: 1.7 % / Num. unique obs: 3033 / CC_1/2: 0.603 / % possible all: 96.9

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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: 2.9→44.166 Å / Cor.coef. F_o:F_c: 0.916 / Cor.coef. F_o:F_c free: 0.843 / SU B: 57.94 / SU ML: 0.491 / Cross valid method: THROUGHOUT / ESU R Free: 0.491
Details: Hydrogens have been added in their riding positions

	R_factor	Num. reflection	% reflection	Selection details
R_free	0.2681	964	5.147 %	RANDOM
R_work	0.2066	17766	-	-
all	0.21	-	-	-
obs	-	18730	96.846 %	-

Solvent computation

Ion probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1 Å / Solvent model: MASK BULK SOLVENT

Displacement parameters

B_iso mean: 52.241 Å²

	B_aniso -1	B_aniso -2	B_aniso -3
1-	-5.382 Å²	4.93 Å²	-0.435 Å²
2-	-	-0.862 Å²	2.522 Å²
3-	-	-	2.759 Å²

Refinement step

Cycle: LAST / Resolution: 2.9→44.166 Å

	Protein	Nucleic acid	Ligand	Solvent	Total
Num. atoms	6287	0	137	127	6551

Refine LS restraints

Refine-ID	Type	Dev ideal	Dev ideal target	Number
X-RAY DIFFRACTION	r_bond_refined_d	0.004	0.016	6784
X-RAY DIFFRACTION	r_bond_other_d	0.001	0.016	6058
X-RAY DIFFRACTION	r_angle_refined_deg	0.865	1.784	9224
X-RAY DIFFRACTION	r_angle_other_deg	0.333	1.565	14015
X-RAY DIFFRACTION	r_dihedral_angle_1_deg	6.7	5.291	824
X-RAY DIFFRACTION	r_dihedral_angle_2_deg	23.151	10	52
X-RAY DIFFRACTION	r_dihedral_angle_3_deg	12.367	10	1076
X-RAY DIFFRACTION	r_dihedral_angle_6_deg	11.731	10	313
X-RAY DIFFRACTION	r_chiral_restr	0.042	0.2	925
X-RAY DIFFRACTION	r_gen_planes_refined	0.003	0.02	7821
X-RAY DIFFRACTION	r_gen_planes_other	0.001	0.02	1595
X-RAY DIFFRACTION	r_nbd_refined	0.175	0.2	1503
X-RAY DIFFRACTION	r_symmetry_nbd_other	0.174	0.2	6286
X-RAY DIFFRACTION	r_nbtor_refined	0.17	0.2	3239
X-RAY DIFFRACTION	r_symmetry_nbtor_other	0.088	0.2	3271
X-RAY DIFFRACTION	r_xyhbond_nbd_refined	0.115	0.2	229
X-RAY DIFFRACTION	r_metal_ion_refined	0.126	0.2	2
X-RAY DIFFRACTION	r_symmetry_nbd_refined	0.144	0.2	12
X-RAY DIFFRACTION	r_nbd_other	0.201	0.2	57
X-RAY DIFFRACTION	r_symmetry_xyhbond_nbd_refined	0.146	0.2	6
X-RAY DIFFRACTION	r_mcbond_it	0.993	2.232	3118
X-RAY DIFFRACTION	r_mcbond_other	0.983	2.228	3110
X-RAY DIFFRACTION	r_mcangle_it	1.752	4.007	3881
X-RAY DIFFRACTION	r_mcangle_other	1.752	4.008	3882
X-RAY DIFFRACTION	r_scbond_it	0.943	2.336	3666
X-RAY DIFFRACTION	r_scbond_other	0.943	2.338	3667
X-RAY DIFFRACTION	r_scangle_it	1.57	4.265	5342
X-RAY DIFFRACTION	r_scangle_other	1.57	4.266	5343
X-RAY DIFFRACTION	r_lrange_it	4.741	26.788	28709
X-RAY DIFFRACTION	r_lrange_other	4.728	26.781	28688

LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 20

Resolution (Å)	R_factor R_free	Num. reflection R_free	R_factor R_work	Num. reflection R_work	R_factor all	Num. reflection all	Fsc free	Fsc work	% reflection obs (%)	WR_factor R_work
2.9-2.975	0.411	64	0.311	1328	0.315	1435	0.891	0.945	97.0035	0.308
2.975-3.056	0.324	63	0.313	1289	0.313	1398	0.936	0.943	96.7096	0.31
3.056-3.144	0.337	60	0.296	1221	0.298	1326	0.928	0.953	96.6063	0.288
3.144-3.241	0.332	75	0.272	1194	0.276	1317	0.935	0.961	96.3554	0.263
3.241-3.346	0.326	75	0.24	1197	0.245	1319	0.95	0.97	96.4367	0.233
3.346-3.463	0.281	58	0.234	1087	0.237	1191	0.95	0.97	96.1377	0.223
3.463-3.593	0.321	55	0.23	1076	0.235	1186	0.942	0.973	95.3626	0.215
3.593-3.739	0.28	67	0.219	1028	0.223	1148	0.958	0.975	95.3833	0.206
3.739-3.903	0.249	60	0.195	1000	0.198	1091	0.966	0.981	97.1586	0.185
3.903-4.092	0.237	51	0.178	987	0.181	1059	0.964	0.983	98.017	0.171
4.092-4.312	0.17	48	0.157	932	0.157	1000	0.981	0.987	98	0.151
4.312-4.571	0.219	40	0.147	860	0.15	928	0.967	0.988	96.9828	0.146
4.571-4.882	0.247	40	0.145	835	0.15	894	0.974	0.988	97.8747	0.145
4.882-5.268	0.241	36	0.153	764	0.157	821	0.963	0.989	97.4421	0.15
5.268-5.763	0.233	46	0.196	693	0.198	758	0.971	0.981	97.4934	0.192
5.763-6.429	0.297	41	0.202	641	0.208	697	0.946	0.977	97.8479	0.205
6.429-7.398	0.29	24	0.197	551	0.201	598	0.95	0.978	96.1538	0.199
7.398-8.998	0.206	25	0.16	503	0.162	535	0.977	0.985	98.6916	0.166
8.998-12.469	0.163	24	0.151	367	0.152	399	0.981	0.987	97.995	0.159
12.469-44.166	0.313	12	0.235	212	0.238	235	0.957	0.96	95.3192	0.261

Refinement TLS params.

Method: refined / Origin x: 0.5439 Å / Origin y: 0.4988 Å / Origin z: -0.2817 Å

	11	12	13	21	22	23	31	32	33
T	0.5619 Å²	-0.3575 Å²	0.1457 Å²	-	0.2371 Å²	-0.0925 Å²	-	-	0.0442 Å²
L	0.8844 °²	0.3494 °²	-0.6077 °²	-	0.4747 °²	-0.3843 °²	-	-	1.1911 °²
S	0.0398 Å °	0.0562 Å °	0.0282 Å °	0.0147 Å °	0.0338 Å °	0.0414 Å °	0.0003 Å °	-0.0248 Å °	-0.0736 Å °

Refinement TLS group

ID	Refine-ID	Refine TLS-ID	Selection	Auth asym-ID	Auth seq-ID
1	X-RAY DIFFRACTION	1	ALL	A	56 - 859
2	X-RAY DIFFRACTION	1		B	1 - 5

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