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

ID or keywords:

Entry

Database: PDB / ID: 9fxu

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 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: 2.25 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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PDBx/mmCIF format	9fxu.cif.gz	827.8 KB	Display	PDBx/mmCIF format
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Validation report

Summary document	9fxu_validation.pdf.gz	1 MB	Display	wwPDB validaton report
Full document	9fxu_full_validation.pdf.gz	1 MB	Display
Data in XML	9fxu_validation.xml.gz	36.6 KB	Display
Data in CIF	9fxu_validation.cif.gz	50.2 KB	Display
Arichive directory	https://data.pdbj.org/pub/pdb/validation_reports/fx/9fxu ftp://data.pdbj.org/pub/pdb/validation_reports/fx/9fxu	HTTPS FTP

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Related structure data

Related structure data	9ftnC 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 Autotaxin

hetero molecules

96.3 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)	53.706, 63.424, 70.306
Angle α, β, γ (deg.)	99.553, 105.153, 99.268
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

alpha-D-mannopyranose-(1-6)-beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1- ...

Type: oligosaccharide / Mass: 748.682 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source

Descriptor	Type	Program
DManpa1-6DManpb1-4DGlcpNAcb1-4DGlcpNAcb1-ROH	Glycam Condensed Sequence	GMML 1.0
WURCS=2.0/3,4,3/[a2122h-1b_1-5_2*NCC/3=O][a1122h-1b_1-5][a1122h-1a_1-5]/1-1-2-3/a4-b1_b4-c1_c6-d1	WURCS	PDB2Glycan 1.1.0
[][D-1-deoxy-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-Manp]{[(6+1)][a-D-Manp]{}}}}	LINUCS	PDB-CARE

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Non-polymers , 7 types, 288 molecules

#3: Chemical	ChemComp-A1IGZ / N-(2-(3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)-6-(1-(methylsulfonyl)piperidin-4-yl)imidazo[1,2-b]pyridazin-2-yl)ethyl)-2-oxo-2,3-dihydrobenzo[d]oxazole-6-carboxamide / N-[2-[3-[[4-(4-fluorophenyl)-1,3-thiazol-2-yl]-methyl-amino]-6-(1-methylsulfonylpiperidin-4-yl)imidazo[1,2-b]pyridazin-2-yl]ethyl]-2-oxidanylidene-3H-1,3-benzoxazole-6-carboxamide Mass: 690.768 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C₃₂H₃₁FN₈O₅S₂ / Feature type: SUBJECT OF INVESTIGATION
#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.: 1 / Source method: obtained synthetically / Formula: I
#7: Chemical	... ChemComp-SCN / THIOCYANATE ION Mass: 58.082 Da / Num. of mol.: 26 / Source method: obtained synthetically / Formula: CNS
#8: Chemical	ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL Mass: 92.094 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C₃H₈O₃
#9: Water	ChemComp-HOH / water Mass: 18.015 Da / Num. of mol.: 255 / 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: 2.4 Å³/Da / Density % sol: 48.66 %
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: 2.4 Å³/Da / Density % sol: 48.66 %

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: 2.25→47.59 Å / Num. obs: 40044 / % possible obs: 97.9 % / Redundancy: 2.7 % / CC_1/2: 0.978 / R_merge(I) obs: 0.091 / R_pim(I) all: 0.068 / R_rim(I) all: 0.114 / Net I/σ(I): 7.3
Reflection shell	Resolution: 2.25→2.32 Å / Redundancy: 2.6 % / Num. unique obs: 3659 / CC_1/2: 0.477 / % possible all: 97.3

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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: 2.25→47.59 Å / Cor.coef. F_o:F_c: 0.963 / Cor.coef. F_o:F_c free: 0.945 / SU B: 15.423 / SU ML: 0.177 / Cross valid method: THROUGHOUT / ESU R: 0.32 / ESU R Free: 0.204
Details: Hydrogens have been added in their riding positions

	R_factor	Num. reflection	% reflection	Selection details
R_free	0.2102	2025	5.057 %	RANDOM
R_work	0.1772	38016	-	-
all	0.179	-	-	-
obs	-	40041	97.864 %	-

Solvent computation

Ion probe radii: 0.7 Å / Shrinkage radii: 0.7 Å / VDW probe radii: 1 Å / Solvent model: MASK BULK SOLVENT

Displacement parameters

B_iso mean: 53.694 Å²

	B_aniso -1	B_aniso -2	B_aniso -3
1-	-0.245 Å²	0.836 Å²	1.627 Å²
2-	-	-0.128 Å²	0.046 Å²
3-	-	-	-0.736 Å²

Refinement step

Cycle: LAST / Resolution: 2.25→47.59 Å

	Protein	Nucleic acid	Ligand	Solvent	Total
Num. atoms	6305	0	192	255	6752

Refine LS restraints

Refine-ID	Type	Dev ideal	Dev ideal target	Number
X-RAY DIFFRACTION	r_bond_refined_d	0.009	0.016	6668
X-RAY DIFFRACTION	r_bond_other_d	0.001	0.016	5975
X-RAY DIFFRACTION	r_angle_refined_deg	1.212	1.784	9016
X-RAY DIFFRACTION	r_angle_other_deg	0.422	1.566	13835
X-RAY DIFFRACTION	r_dihedral_angle_1_deg	10.551	5.291	824
X-RAY DIFFRACTION	r_dihedral_angle_2_deg	23.451	10	13
X-RAY DIFFRACTION	r_dihedral_angle_3_deg	13.576	10	1080
X-RAY DIFFRACTION	r_dihedral_angle_6_deg	15.297	10	314
X-RAY DIFFRACTION	r_chiral_restr	0.059	0.2	929
X-RAY DIFFRACTION	r_gen_planes_refined	0.005	0.02	7659
X-RAY DIFFRACTION	r_gen_planes_other	0.001	0.02	1557
X-RAY DIFFRACTION	r_nbd_refined	0.208	0.2	1462
X-RAY DIFFRACTION	r_symmetry_nbd_other	0.192	0.2	6099
X-RAY DIFFRACTION	r_nbtor_refined	0.182	0.2	3248
X-RAY DIFFRACTION	r_symmetry_nbtor_other	0.084	0.2	3456
X-RAY DIFFRACTION	r_xyhbond_nbd_refined	0.156	0.2	330
X-RAY DIFFRACTION	r_symmetry_xyhbond_nbd_other	0.069	0.2	2
X-RAY DIFFRACTION	r_metal_ion_refined	0.163	0.2	6
X-RAY DIFFRACTION	r_symmetry_nbd_refined	0.15	0.2	21
X-RAY DIFFRACTION	r_nbd_other	0.222	0.2	92
X-RAY DIFFRACTION	r_symmetry_xyhbond_nbd_refined	0.162	0.2	5
X-RAY DIFFRACTION	r_mcbond_it	2.298	3.531	3142
X-RAY DIFFRACTION	r_mcbond_other	2.024	3.504	3116
X-RAY DIFFRACTION	r_mcangle_it	3.234	6.293	3888
X-RAY DIFFRACTION	r_mcangle_other	3.235	6.294	3889
X-RAY DIFFRACTION	r_scbond_it	2.8	3.837	3526
X-RAY DIFFRACTION	r_scbond_other	2.68	3.819	3513
X-RAY DIFFRACTION	r_scangle_it	4.485	6.921	5128
X-RAY DIFFRACTION	r_scangle_other	4.29	6.895	5115
X-RAY DIFFRACTION	r_lrange_it	8.233	43.273	29316
X-RAY DIFFRACTION	r_lrange_other	8.206	43.227	29218

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 (%)
2.25-2.308	0.303	132	0.292	2807	X-RAY DIFFRACTION	97.4146
2.308-2.371	0.341	155	0.281	2688	X-RAY DIFFRACTION	96.6021
2.371-2.44	0.293	157	0.256	2688	X-RAY DIFFRACTION	97.9683
2.44-2.515	0.287	133	0.236	2528	X-RAY DIFFRACTION	97.9389
2.515-2.597	0.262	139	0.232	2520	X-RAY DIFFRACTION	98.0096
2.597-2.688	0.263	126	0.218	2445	X-RAY DIFFRACTION	97.7567
2.688-2.789	0.213	118	0.195	2331	X-RAY DIFFRACTION	98.3139
2.789-2.903	0.184	117	0.175	2254	X-RAY DIFFRACTION	97.8943
2.903-3.031	0.225	118	0.175	2184	X-RAY DIFFRACTION	98.1663
3.031-3.178	0.191	129	0.177	2085	X-RAY DIFFRACTION	98.3126
3.178-3.35	0.201	106	0.176	1944	X-RAY DIFFRACTION	98.2742
3.35-3.552	0.218	104	0.172	1850	X-RAY DIFFRACTION	97.9449
3.552-3.795	0.183	89	0.163	1755	X-RAY DIFFRACTION	98.5043
3.795-4.097	0.155	63	0.148	1652	X-RAY DIFFRACTION	98.2245
4.097-4.485	0.166	79	0.129	1515	X-RAY DIFFRACTION	98.032
4.485-5.009	0.186	73	0.131	1335	X-RAY DIFFRACTION	97.5069
5.009-5.773	0.257	57	0.167	1198	X-RAY DIFFRACTION	97.5894
5.773-7.045	0.214	57	0.184	1028	X-RAY DIFFRACTION	98.3681
7.045-9.856	0.172	47	0.146	769	X-RAY DIFFRACTION	97.9592
9.856-47.59	0.153	26	0.16	440	X-RAY DIFFRACTION	95.8848

Refinement TLS params.

Method: refined / Origin x: 0.4755 Å / Origin y: 0.4793 Å / Origin z: -0.3629 Å

	11	12	13	21	22	23	31	32	33
T	0.0596 Å²	-0.0008 Å²	-0.0402 Å²	-	0.0045 Å²	0.0118 Å²	-	-	0.1194 Å²
L	1.438 °²	0.4929 °²	-0.9273 °²	-	0.6914 °²	-0.4665 °²	-	-	1.7726 °²
S	0.0261 Å °	0.0608 Å °	-0.0351 Å °	0.0451 Å °	0.0393 Å °	0.0241 Å °	-0.0133 Å °	-0.0539 Å °	-0.0654 Å °

Refinement TLS group

Selection: ALL

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