PDB-7z3k: Autotaxin in complex with orthosteric site-binder CpdA

ID or keywords:

Entry

Database: PDB / ID: 7z3k

Title

Autotaxin in complex with orthosteric site-binder CpdA

Components

Isoform 2 of Ectonucleotide pyrophosphatase/phosphodiesterase family member 2

Keywords

HYDROLASE /

ENPP2 /

lysophosphatidic acid / lipid chaperone / / pulmonary fibrosis /

GPCR / drug development / small-molecule inhibitor

Function / homology

Function and homology information

response to polycyclic arene /

alkylglycerophosphoethanolamine phosphodiesterase / sphingolipid catabolic process / phospholipid catabolic process / phosphatidylcholine catabolic process /

lysophospholipase activity / positive regulation of lamellipodium morphogenesis /

phosphodiesterase I activity / scavenger receptor activity /

alkylglycerophosphoethanolamine phosphodiesterase activity ...
Similarity search - Function

Biological species

Rattus norvegicus (Norway rat)

Method

X-RAY DIFFRACTION /

SYNCHROTRON /

MOLECULAR REPLACEMENT / Resolution: 2 Å

Authors

Salgado-Polo, F. / Ford, P. / Heckmann, B. / Perrakis, A.

Funding support

1items

Citation

Journal: Cell Chem Biol / Year: 2023
Title: Autotaxin facilitates selective LPA receptor signaling.
Authors: Salgado-Polo, F. / Borza, R. / Matsoukas, M.T. / Marsais, F. / Jagerschmidt, C. / Waeckel, L. / Moolenaar, W.H. / Ford, P. / Heckmann, B. / Perrakis, A.

History

Deposition	Mar 2, 2022	Deposition site: PDBE / Processing site: PDBE
Revision 1.0	Jan 25, 2023	Provider: repository / Type: Initial release
Revision 1.1	Feb 1, 2023	Group: Database references / Category: citation Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.2	Feb 7, 2024	Group: Data collection / Refinement description Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

Structure viewer	Molecule: MolmilJmol/JSmol

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Download

PDBx/mmCIF format	7z3k.cif.gz	604.6 KB	Display	PDBx/mmCIF format
PDB format	pdb7z3k.ent.gz		Display	PDB format
PDBx/mmJSON format	7z3k.json.gz		Tree view	PDBx/mmJSON format
Others	Other downloads

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Validation report

Arichive directory	https://data.pdbj.org/pub/pdb/validation_reports/z3/7z3k ftp://data.pdbj.org/pub/pdb/validation_reports/z3/7z3k	HTTPS FTP

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Related structure data

Related structure data	7z3lC 2xr9S S: Starting model for refinement 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

AAA: Isoform 2 of Ectonucleotide pyrophosphatase/phosphodiesterase family member 2

hetero molecules

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

1

Idetical with deposited unit
defined by author
Evidence: gel filtration

Unit cell

Length a, b, c (Å)	53.662, 62.530, 63.638
Angle α, β, γ (deg.)	104.159, 98.572, 93.153
Int Tables number	1
Space group name H-M	P1

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Protein , 1 types, 1 molecules AAA

#1: Protein	Isoform 2 of Ectonucleotide pyrophosphatase/phosphodiesterase family member 2 / E-NPP 2 / Autotaxin / Extracellular lysophospholipase D / LysoPLD Mass: 92590.125 Da / Num. of mol.: 1 / Mutation: N53A N410A N806A Source method: isolated from a genetically manipulated source Source: (gene. exp.) Rattus norvegicus (Norway rat) / Gene: Enpp2, Atx, Npps2 / Plasmid: pcDNA5.1 / Cell line (production host): HEK293T / Production host: Homo sapiens (human) References: UniProt: Q64610, alkylglycerophosphoethanolamine phosphodiesterase

#1: Protein

Isoform 2 of Ectonucleotide pyrophosphatase/phosphodiesterase family member 2 / E-NPP 2 / Autotaxin / Extracellular lysophospholipase D / LysoPLD

Mass: 92590.125 Da / Num. of mol.: 1 / Mutation: N53A N410A N806A
Source method: isolated from a genetically manipulated source
Source: (gene. exp.)

Rattus norvegicus (Norway rat) / Gene: Enpp2, Atx, Npps2 / Plasmid: pcDNA5.1 / Cell line (production host): HEK293T / Production host:

Homo sapiens (human)
References: UniProt: Q64610,

alkylglycerophosphoethanolamine phosphodiesterase

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Sugars , 2 types, 2 molecules

#2: Polysaccharide

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

Type: oligosaccharide

/ Mass: 383.349 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source

Descriptor	Type	Program
DManpb1-4DGlcpNAcb1-ROH	Glycam Condensed Sequence	GMML 1.0
WURCS=2.0/2,2,1/[a2122h-1b_1-5_2*NCC/3=O][a1122h-1b_1-5]/1-2/a4-b1	WURCS	PDB2Glycan 1.1.0
[][D-1-deoxy-GlcpNAc]{[(4+1)][b-D-Manp]{}}	LINUCS	PDB-CARE

#3: 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 /

N-Acetylglucosamine

Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C₈H₁₅NO₆

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 , 9 types, 566 molecules

#4: Chemical	ChemComp-ZN / ZINC ION Mass: 65.409 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Zn
#5: Chemical	ChemComp-5JK / 7alpha-hydroxycholesterol / (3beta,7alpha,9beta,14beta)-cholest-5-ene-3,7-diol / 7α-Hydroxycholesterol Mass: 402.653 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C₂₇H₄₆O₂
#6: Chemical	ChemComp-CA / CALCIUM ION Mass: 40.078 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Ca
#7: Chemical	ChemComp-IOD / IODIDE ION / Iodide Mass: 126.904 Da / Num. of mol.: 17 / Source method: obtained synthetically / Formula: I
#8: Chemical	ChemComp-SCN / THIOCYANATE ION / Thiocyanate Mass: 58.082 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: CNS
#9: Chemical	ChemComp-NA / SODIUM ION Mass: 22.990 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Na
#10: Chemical	ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL / Glycerol Mass: 92.094 Da / Num. of mol.: 9 / Source method: obtained synthetically / Formula: C₃H₈O₃
#11: Chemical	ChemComp-IA0 / [(2~{S},4~{R})-4-[2-[(3,5-dimethylphenyl)amino]-5,7-dihydropyrrolo[3,4-d]pyrimidin-6-yl]-2-methyl-piperidin-1-yl]-(6-fluoranyl-1~{H}-benzotriazol-5-yl)methanone Mass: 500.571 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C₂₇H₂₉FN₈O / Feature type: SUBJECT OF INVESTIGATION
#12: Water	ChemComp-HOH / water / Water Mass: 18.015 Da / Num. of mol.: 527 / 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: 2.24 Å³/Da / Density % sol: 45 %
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: 2.24 Å³/Da / Density % sol: 45 %

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:

SLS

/ Beamline: X06DA / Wavelength: 0.999995 Å

Detector

Type: DECTRIS PILATUS 2M-F / Detector: PIXEL / Date: Jul 5, 2020

Radiation

Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray

Radiation wavelength

Wavelength: 0.999995 Å / Relative weight: 1

Reflection

Resolution: 2→43.68 Å / Num. obs: 52303 / % possible obs: 98 % / Redundancy: 3.2 % / CC_1/2: 0.985 / R_merge(I) obs: 0.137 / R_pim(I) all: 0.137 / R_rim(I) all: 0.194 / Net I/σ(I): 5.6

Reflection shell

Diffraction-ID: 1

Resolution (Å)	Redundancy (%)	R_merge(I) obs	Num. unique obs	CC_1/2	R_pim(I) all	R_rim(I) all	% possible all
8.94-43.68	3.3	0.04	584	0.996	0.04	0.056	99
2-2.05	3.1	0.798	3841	0.437	0.798	1.129	96.9

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Processing

Software

Name	Version	Classification
REFMAC	5.8.0267	refinement
REFMAC	5.8.0267	refinement
Aimless		data scaling
Coot		model building
PHASER		phasing
MolProbity		model building

Refinement

Method to determine structure:

MOLECULAR REPLACEMENT
Starting model: 2xr9

2xr9

Resolution: 2→43.68 Å / Cor.coef. F_o:F_c: 0.942 / Cor.coef. F_o:F_c free: 0.912 / SU B: 12.667 / SU ML: 0.173 / Cross valid method: FREE R-VALUE / ESU R: 0.24 / ESU R Free: 0.188
Details: Hydrogens have been added in their riding positions

	R_factor	Num. reflection	% reflection
R_free	0.2422	2646	5.059 %
R_work	0.202	49655	-
all	0.204	-	-
obs	-	52301	97.999 %

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: 26.899 Å²

	B_aniso -1	B_aniso -2	B_aniso -3
1-	1.415 Å²	1.245 Å²	1.265 Å²
2-	-	-1.99 Å²	-1.242 Å²
3-	-	-	0.588 Å²

Refinement step

Cycle: LAST / Resolution: 2→43.68 Å

	Protein	Nucleic acid	Ligand	Solvent	Total
Num. atoms	6391	0	199	527	7117

Refine LS restraints

Refine-ID	Type	Dev ideal	Dev ideal target	Number
X-RAY DIFFRACTION	r_bond_refined_d	0.003	0.013	6774
X-RAY DIFFRACTION	r_bond_other_d	0.001	0.015	6152
X-RAY DIFFRACTION	r_angle_refined_deg	1.218	1.663	9182
X-RAY DIFFRACTION	r_angle_other_deg	1.084	1.587	14247
X-RAY DIFFRACTION	r_dihedral_angle_1_deg	6.853	5	792
X-RAY DIFFRACTION	r_dihedral_angle_2_deg	30.592	21.486	370
X-RAY DIFFRACTION	r_dihedral_angle_3_deg	12.76	15	1102
X-RAY DIFFRACTION	r_dihedral_angle_4_deg	16.136	15	48
X-RAY DIFFRACTION	r_chiral_restr	0.046	0.2	849
X-RAY DIFFRACTION	r_gen_planes_refined	0.003	0.02	7491
X-RAY DIFFRACTION	r_gen_planes_other	0.001	0.02	1576
X-RAY DIFFRACTION	r_nbd_refined	0.179	0.2	1393
X-RAY DIFFRACTION	r_symmetry_nbd_other	0.17	0.2	6132
X-RAY DIFFRACTION	r_nbtor_refined	0.159	0.2	3205
X-RAY DIFFRACTION	r_symmetry_nbtor_other	0.073	0.2	3034
X-RAY DIFFRACTION	r_xyhbond_nbd_refined	0.111	0.2	528
X-RAY DIFFRACTION	r_symmetry_xyhbond_nbd_other	0.019	0.2	1
X-RAY DIFFRACTION	r_metal_ion_refined	0.095	0.2	11
X-RAY DIFFRACTION	r_symmetry_nbd_refined	0.155	0.2	28
X-RAY DIFFRACTION	r_nbd_other	0.168	0.2	122
X-RAY DIFFRACTION	r_symmetry_xyhbond_nbd_refined	0.153	0.2	12
X-RAY DIFFRACTION	r_mcbond_it	0.394	0.666	3172
X-RAY DIFFRACTION	r_mcbond_other	0.389	0.663	3167
X-RAY DIFFRACTION	r_mcangle_it	0.728	0.992	3954
X-RAY DIFFRACTION	r_mcangle_other	0.727	0.992	3954
X-RAY DIFFRACTION	r_scbond_it	0.362	0.711	3602
X-RAY DIFFRACTION	r_scbond_other	0.362	0.712	3603
X-RAY DIFFRACTION	r_scangle_it	0.503	1.04	5226
X-RAY DIFFRACTION	r_scangle_other	0.503	1.04	5227
X-RAY DIFFRACTION	r_lrange_it	6.454	8.916	7760
X-RAY DIFFRACTION	r_lrange_other	6.386	8.347	7656

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	0.279	223	0.29	3617	X-RAY DIFFRACTION	96.8718
2.052-2.108	0.29	196	0.271	3549	X-RAY DIFFRACTION	97.3739
2.108-2.169	0.273	204	0.251	3421	X-RAY DIFFRACTION	96.8733
2.169-2.236	0.28	202	0.261	3326	X-RAY DIFFRACTION	96.8167
2.236-2.309	0.287	184	0.252	3237	X-RAY DIFFRACTION	98.0229
2.309-2.39	0.295	166	0.23	3140	X-RAY DIFFRACTION	97.695
2.39-2.48	0.256	167	0.238	3061	X-RAY DIFFRACTION	97.4638
2.48-2.581	0.258	135	0.229	2967	X-RAY DIFFRACTION	97.8549
2.581-2.696	0.277	131	0.215	2851	X-RAY DIFFRACTION	97.9632
2.696-2.827	0.242	137	0.191	2719	X-RAY DIFFRACTION	98.1443
2.827-2.979	0.212	137	0.192	2579	X-RAY DIFFRACTION	98.4415
2.979-3.16	0.286	108	0.193	2437	X-RAY DIFFRACTION	98.5288
3.16-3.377	0.212	129	0.17	2297	X-RAY DIFFRACTION	98.9396
3.377-3.647	0.194	113	0.16	2138	X-RAY DIFFRACTION	99.1193
3.647-3.994	0.184	91	0.158	1977	X-RAY DIFFRACTION	99.0896
3.994-4.463	0.197	99	0.149	1796	X-RAY DIFFRACTION	98.5952
4.463-5.148	0.221	60	0.16	1588	X-RAY DIFFRACTION	99.6372
5.148-6.294	0.24	64	0.202	1349	X-RAY DIFFRACTION	99.507
6.294-8.854	0.245	66	0.21	1036	X-RAY DIFFRACTION	99.6383
8.854-43.68	0.255	34	0.214	570	X-RAY DIFFRACTION	99.179

Refinement TLS params.

Method: refined / Origin x: 0.0101 Å / Origin y: -0.0737 Å / Origin z: 0.1439 Å

	11	12	13	21	22	23	31	32	33
T	0.0402 Å²	-0.0883 Å²	-0.0624 Å²	-	0.2116 Å²	0.144 Å²	-	-	0.1008 Å²
L	0.9619 °²	0.2184 °²	0.5765 °²	-	0.9092 °²	0.4908 °²	-	-	1.4673 °²
S	-0.0158 Å °	0.0288 Å °	-0.0112 Å °	0.0364 Å °	0.0206 Å °	-0.0299 Å °	0.0192 Å °	0.0667 Å °	-0.0048 Å °

Refinement TLS group

ID	Refine-ID	Refine TLS-ID	Selection	Auth asym-ID	Auth seq-ID
1	X-RAY DIFFRACTION	1	ALL	AAA	56 - 860
2	X-RAY DIFFRACTION	1	ALL	AaA	901
3	X-RAY DIFFRACTION	1	ALL	AbA	945
4	X-RAY DIFFRACTION	1	ALL	AcA	938
5	X-RAY DIFFRACTION	1	ALL	AdA	904
6	X-RAY DIFFRACTION	1	ALL	AeA	905
7	X-RAY DIFFRACTION	1	ALL	AfA	906
8	X-RAY DIFFRACTION	1	ALL	AgA	907
9	X-RAY DIFFRACTION	1	ALL	AhA	908
10	X-RAY DIFFRACTION	1	ALL	AiA	909
11	X-RAY DIFFRACTION	1	ALL	AjA	910
12	X-RAY DIFFRACTION	1	ALL	AkA	911
13	X-RAY DIFFRACTION	1	ALL	AlA	913
14	X-RAY DIFFRACTION	1	ALL	AmA	915
15	X-RAY DIFFRACTION	1	ALL	AnA	916
16	X-RAY DIFFRACTION	1	ALL	AoA	918
17	X-RAY DIFFRACTION	1	ALL	ApA	919
18	X-RAY DIFFRACTION	1	ALL	AqA	922
19	X-RAY DIFFRACTION	1	ALL	ArA	923
20	X-RAY DIFFRACTION	1	ALL	AsA	925
21	X-RAY DIFFRACTION	1	ALL	AtA	928
22	X-RAY DIFFRACTION	1	ALL	AuA	929
23	X-RAY DIFFRACTION	1	ALL	AvA	930
24	X-RAY DIFFRACTION	1	ALL	AwA	931
25	X-RAY DIFFRACTION	1	ALL	AxA	932
26	X-RAY DIFFRACTION	1	ALL	AyA	933
27	X-RAY DIFFRACTION	1	ALL	AzA	934
28	X-RAY DIFFRACTION	1	ALL	ABA	935
29	X-RAY DIFFRACTION	1	ALL	ACA	936
30	X-RAY DIFFRACTION	1	ALL	ADA	937
31	X-RAY DIFFRACTION	1	ALL	AEA	939
32	X-RAY DIFFRACTION	1	ALL	AFA	941
33	X-RAY DIFFRACTION	1	ALL	AGA	943
34	X-RAY DIFFRACTION	1	ALL	AHA	944

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