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

ID or keywords:

Entry

Database: PDB / ID: 9fxw

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: 1.95 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	9fxw.cif.gz	826.8 KB	Display	PDBx/mmCIF format
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Validation report

Summary document	9fxw_validation.pdf.gz	1.1 MB	Display	wwPDB validaton report
Full document	9fxw_full_validation.pdf.gz	1.1 MB	Display
Data in XML	9fxw_validation.xml.gz	39.8 KB	Display
Data in CIF	9fxw_validation.cif.gz	54.4 KB	Display
Arichive directory	https://data.pdbj.org/pub/pdb/validation_reports/fx/9fxw ftp://data.pdbj.org/pub/pdb/validation_reports/fx/9fxw	HTTPS FTP

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Related structure data

Related structure data	9ftnC 9fxuC 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

99.1 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)	63.542, 90.729, 77.678
Angle α, β, γ (deg.)	90.000, 109.519, 90.000
Int Tables number	4
Space group name H-M	P12₁1

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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)-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 genetically manipulated source

Descriptor	Type	Program
DManpa1-6DManpa1-6DManpb1-4DGlcpNAcb1-4DGlcpNAcb1-	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_c6-d1_d6-e1	WURCS	PDB2Glycan 1.1.0
[]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-Manp]{[(6+1)][a-D-Manp]{[(6+1)][a-D-Manp]{}}}}}}	LINUCS	PDB-CARE

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Non-polymers , 7 types, 422 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.: 15 / Source method: obtained synthetically / Formula: I
#6: Chemical	ChemComp-A1IG0 / N-(3-(3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)-6-(1-(methylsulfonyl)piperidin-4-yl)imidazo[1,2-b]pyridazin-2-yl)propyl)-2-oxo-2,3-dihydrobenzo[d]oxazole-6-carboxamide / N-[3-[3-[[4-(4-fluorophenyl)-1,3-thiazol-2-yl]-methyl-amino]-6-(1-methylsulfonylpiperidin-4-yl)imidazo[1,2-b]pyridazin-2-yl]propyl]-2-oxidanylidene-3H-1,3-benzoxazole-6-carboxamide Mass: 704.794 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C₃₃H₃₃FN₈O₅S₂
#7: Chemical	... ChemComp-SCN / THIOCYANATE ION Mass: 58.082 Da / Num. of mol.: 30 / Source method: obtained synthetically / Formula: CNS
#8: Chemical	ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL Mass: 92.094 Da / Num. of mol.: 9 / Source method: obtained synthetically / Formula: C₃H₈O₃
#9: Water	ChemComp-HOH / water Mass: 18.015 Da / Num. of mol.: 364 / 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: 2.1 Å³/Da / Density % sol: 42 %
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: 2.1 Å³/Da / Density % sol: 42 %

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: 1.95→45.36 Å / Num. obs: 60013 / % possible obs: 99.1 % / Redundancy: 3.1 % / CC_1/2: 0.995 / R_merge(I) obs: 0.095 / R_pim(I) all: 0.064 / R_rim(I) all: 0.114 / Net I/σ(I): 8.7
Reflection shell	Resolution: 1.95→2 Å / Redundancy: 3 % / Num. unique obs: 4238 / CC_1/2: 0.592 / % possible all: 99.4

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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: 1.95→38.592 Å / Cor.coef. F_o:F_c: 0.962 / Cor.coef. F_o:F_c free: 0.949 / SU B: 8.238 / SU ML: 0.109 / Cross valid method: THROUGHOUT / ESU R: 0.169 / ESU R Free: 0.14
Details: Hydrogens have been added in their riding positions

	R_factor	Num. reflection	% reflection	Selection details
R_free	0.2012	2898	4.831 %	RANDOM
R_work	0.1742	57090	-	-
all	0.175	-	-	-
obs	-	59988	99.023 %	-

Solvent computation

Ion probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.1 Å / Solvent model: MASK BULK SOLVENT

Displacement parameters

B_iso mean: 31.492 Å²

	B_aniso -1	B_aniso -2	B_aniso -3
1-	-0.445 Å²	-0 Å²	-0.572 Å²
2-	-	1.905 Å²	-0 Å²
3-	-	-	-0.843 Å²

Refinement step

Cycle: LAST / Resolution: 1.95→38.592 Å

	Protein	Nucleic acid	Ligand	Solvent	Total
Num. atoms	6292	0	272	364	6928

Refine LS restraints

Refine-ID	Type	Dev ideal	Dev ideal target	Number
X-RAY DIFFRACTION	r_bond_refined_d	0.006	0.016	6741
X-RAY DIFFRACTION	r_bond_other_d	0.001	0.016	6030
X-RAY DIFFRACTION	r_angle_refined_deg	1.094	1.782	9102
X-RAY DIFFRACTION	r_angle_other_deg	0.401	1.566	13971
X-RAY DIFFRACTION	r_dihedral_angle_1_deg	9.324	5.29	828
X-RAY DIFFRACTION	r_dihedral_angle_2_deg	19.272	10	13
X-RAY DIFFRACTION	r_dihedral_angle_3_deg	13.337	10	1078
X-RAY DIFFRACTION	r_dihedral_angle_6_deg	15.862	10	314
X-RAY DIFFRACTION	r_chiral_restr	0.056	0.2	931
X-RAY DIFFRACTION	r_gen_planes_refined	0.004	0.02	7695
X-RAY DIFFRACTION	r_gen_planes_other	0.001	0.02	1565
X-RAY DIFFRACTION	r_nbd_refined	0.202	0.2	1454
X-RAY DIFFRACTION	r_symmetry_nbd_other	0.192	0.2	6052
X-RAY DIFFRACTION	r_nbtor_refined	0.178	0.2	3280
X-RAY DIFFRACTION	r_symmetry_nbtor_other	0.082	0.2	3334
X-RAY DIFFRACTION	r_xyhbond_nbd_refined	0.156	0.2	427
X-RAY DIFFRACTION	r_symmetry_xyhbond_nbd_other	0.033	0.2	2
X-RAY DIFFRACTION	r_metal_ion_refined	0.145	0.2	6
X-RAY DIFFRACTION	r_symmetry_nbd_refined	0.191	0.2	21
X-RAY DIFFRACTION	r_nbd_other	0.194	0.2	69
X-RAY DIFFRACTION	r_symmetry_xyhbond_nbd_refined	0.142	0.2	7
X-RAY DIFFRACTION	r_mcbond_it	2.242	2.394	3154
X-RAY DIFFRACTION	r_mcbond_other	2.016	2.371	3123
X-RAY DIFFRACTION	r_mcangle_it	3.059	4.254	3902
X-RAY DIFFRACTION	r_mcangle_other	3.063	4.256	3903
X-RAY DIFFRACTION	r_scbond_it	3.567	2.858	3587
X-RAY DIFFRACTION	r_scbond_other	3.567	2.858	3586
X-RAY DIFFRACTION	r_scangle_it	5.434	5.063	5200
X-RAY DIFFRACTION	r_scangle_other	5.434	5.061	5199
X-RAY DIFFRACTION	r_lrange_it	7.934	26.9	7773
X-RAY DIFFRACTION	r_lrange_other	7.894	26.858	7733

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
1.95-2.001	0.281	222	0.282	4213	0.282	4462	0.939	0.939	99.3949	0.279
2.001-2.055	0.258	215	0.264	4138	0.264	4365	0.951	0.948	99.7251	0.258
2.055-2.115	0.263	224	0.24	3965	0.241	4201	0.951	0.958	99.7144	0.229
2.115-2.179	0.262	200	0.219	3872	0.221	4081	0.953	0.966	99.7795	0.206
2.179-2.251	0.192	192	0.195	3750	0.195	3958	0.974	0.974	99.5958	0.18
2.251-2.329	0.193	194	0.185	3660	0.185	3865	0.974	0.977	99.7154	0.168
2.329-2.417	0.187	187	0.176	3510	0.176	3711	0.976	0.98	99.6227	0.157
2.417-2.515	0.223	164	0.168	3388	0.17	3571	0.971	0.982	99.4679	0.149
2.515-2.627	0.196	142	0.166	3254	0.167	3423	0.978	0.983	99.2112	0.146
2.627-2.754	0.199	150	0.152	3116	0.154	3319	0.979	0.986	98.4031	0.135
2.754-2.902	0.183	153	0.15	2947	0.152	3119	0.974	0.986	99.3908	0.134
2.902-3.077	0.202	141	0.143	2793	0.146	2949	0.975	0.987	99.4913	0.129
3.077-3.288	0.178	131	0.144	2637	0.146	2792	0.981	0.988	99.1404	0.133
3.288-3.55	0.181	125	0.151	2443	0.152	2589	0.981	0.987	99.1889	0.143
3.55-3.885	0.175	111	0.15	2244	0.151	2390	0.982	0.987	98.5356	0.145
3.885-4.338	0.175	109	0.138	2024	0.14	2174	0.981	0.989	98.1141	0.137
4.338-4.999	0.168	102	0.147	1750	0.148	1929	0.985	0.987	96.0083	0.148
4.999-6.097	0.261	44	0.206	1536	0.208	1632	0.972	0.979	96.8137	0.207
6.097-8.517	0.21	57	0.225	1186	0.224	1286	0.98	0.974	96.6563	0.228
8.517-38.592	0.259	35	0.213	663	0.215	756	0.966	0.975	92.328	0.228

Refinement TLS params.

Method: refined / Origin x: 2.8807 Å / Origin y: -0.1418 Å / Origin z: 19.1441 Å

	11	12	13	21	22	23	31	32	33
T	0.0166 Å²	-0.0102 Å²	-0.0093 Å²	-	0.0414 Å²	-0.0005 Å²	-	-	0.0065 Å²
L	0.3245 °²	-0.0431 °²	0.2456 °²	-	0.2045 °²	-0.1123 °²	-	-	0.8786 °²
S	-0.0147 Å °	-0.0059 Å °	0.0055 Å °	0.0039 Å °	0.014 Å °	-0.0067 Å °	-0.0112 Å °	-0.0177 Å °	0.0008 Å °

Refinement TLS group

Selection: ALL

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