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- PDB-6leh: Crystal structure of Autotaxin in complex with an inhibitor -

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Basic information

Entry
Database: PDB / ID: 6leh
TitleCrystal structure of Autotaxin in complex with an inhibitor
ComponentsEctonucleotide pyrophosphatase/phosphodiesterase family member 2
KeywordsHYDROLASE
Function / homology
Function and homology information


dinucleotide phosphatase activity / alkylglycerophosphoethanolamine phosphodiesterase / sphingolipid catabolic process / phospholipase D / phosphatidylcholine catabolic process / phospholipase D activity / positive regulation of lamellipodium morphogenesis / lysophospholipase activity / phosphodiesterase I activity / scavenger receptor activity ...dinucleotide phosphatase activity / alkylglycerophosphoethanolamine phosphodiesterase / sphingolipid catabolic process / phospholipase D / phosphatidylcholine catabolic process / phospholipase D activity / positive regulation of lamellipodium morphogenesis / lysophospholipase activity / phosphodiesterase I activity / scavenger receptor activity / alkylglycerophosphoethanolamine phosphodiesterase activity / polysaccharide binding / negative regulation of cell-matrix adhesion / positive regulation of oligodendrocyte differentiation / positive regulation of epithelial cell migration / positive regulation of focal adhesion assembly / estrous cycle / phospholipid metabolic process / positive regulation of substrate adhesion-dependent cell spreading / cell chemotaxis / positive regulation of peptidyl-tyrosine phosphorylation / nucleic acid binding / immune response / positive regulation of cell population proliferation / calcium ion binding / extracellular space / zinc ion binding / plasma membrane
Similarity search - Function
Somatomedin B domain, chordata / Somatomedin B -like domains / Somatomedin B domain / Somatomedin B-like domain superfamily / Somatomedin B domain / Somatomedin B domain (SMB) signature. / Somatomedin B (SMB) domain profile. / Type I phosphodiesterase/nucleotide pyrophosphatase/phosphate transferase / Type I phosphodiesterase / nucleotide pyrophosphatase / Extracellular Endonuclease, subunit A ...Somatomedin B domain, chordata / Somatomedin B -like domains / Somatomedin B domain / Somatomedin B-like domain superfamily / Somatomedin B domain / Somatomedin B domain (SMB) signature. / Somatomedin B (SMB) domain profile. / Type I phosphodiesterase/nucleotide pyrophosphatase/phosphate transferase / Type I phosphodiesterase / nucleotide pyrophosphatase / Extracellular Endonuclease, subunit A / DNA/RNA non-specific endonuclease / DNA/RNA non-specific endonuclease / DNA/RNA non-specific endonuclease / DNA/RNA non-specific endonuclease / DNA/RNA non-specific endonuclease superfamily / His-Me finger superfamily / Alkaline-phosphatase-like, core domain superfamily
Similarity search - Domain/homology
Chem-EAR / : / Autotaxin
Similarity search - Component
Biological speciesMus musculus (house mouse)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2 Å
AuthorsNishimasu, H. / Osamu, N.
CitationJournal: J.Med.Chem. / Year: 2020
Title: Identification of PotentIn VivoAutotaxin Inhibitors that Bind to Both Hydrophobic Pockets and Channels in the Catalytic Domain.
Authors: Kawaguchi, M. / Okabe, T. / Okudaira, S. / Hama, K. / Kano, K. / Nishimasu, H. / Nakagawa, H. / Ishitani, R. / Kojima, H. / Nureki, O. / Aoki, J. / Nagano, T.
History
DepositionNov 25, 2019Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Mar 18, 2020Provider: repository / Type: Initial release
Revision 2.0Apr 8, 2020Group: Advisory / Atomic model ...Advisory / Atomic model / Database references / Derived calculations / Polymer sequence / Source and taxonomy / Structure summary
Category: atom_site / citation ...atom_site / citation / entity / entity_poly / entity_poly_seq / entity_src_gen / pdbx_poly_seq_scheme / pdbx_struct_conn_angle / pdbx_struct_sheet_hbond / pdbx_unobs_or_zero_occ_atoms / pdbx_unobs_or_zero_occ_residues / struct_conf / struct_conn / struct_ref_seq / struct_ref_seq_dif / struct_sheet_range / struct_site_gen
Item: _atom_site.label_seq_id / _citation.journal_volume ..._atom_site.label_seq_id / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.title / _entity.formula_weight / _entity_poly.pdbx_seq_one_letter_code / _entity_poly.pdbx_seq_one_letter_code_can / _entity_src_gen.pdbx_end_seq_num / _pdbx_struct_conn_angle.ptnr1_label_seq_id / _pdbx_struct_conn_angle.ptnr3_label_seq_id / _pdbx_struct_sheet_hbond.range_1_label_seq_id / _pdbx_struct_sheet_hbond.range_2_label_seq_id / _pdbx_unobs_or_zero_occ_atoms.label_seq_id / _struct_conf.beg_label_seq_id / _struct_conf.end_label_seq_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr2_label_seq_id / _struct_ref_seq.seq_align_end / _struct_sheet_range.beg_label_seq_id / _struct_sheet_range.end_label_seq_id / _struct_site_gen.label_seq_id
Revision 3.0Jul 29, 2020Group: Atomic model / Data collection ...Atomic model / Data collection / Derived calculations / Structure summary
Category: atom_site / chem_comp ...atom_site / chem_comp / entity / pdbx_branch_scheme / pdbx_chem_comp_identifier / pdbx_entity_branch / pdbx_entity_branch_descriptor / pdbx_entity_branch_link / pdbx_entity_branch_list / pdbx_entity_nonpoly / pdbx_nonpoly_scheme / pdbx_struct_assembly_gen / pdbx_struct_conn_angle / struct_asym / struct_conn / struct_conn_type / struct_site / struct_site_gen
Item: _atom_site.auth_asym_id / _atom_site.auth_seq_id ..._atom_site.auth_asym_id / _atom_site.auth_seq_id / _atom_site.label_asym_id / _atom_site.label_entity_id / _chem_comp.name / _entity.formula_weight / _entity.pdbx_description / _entity.pdbx_number_of_molecules / _entity.type / _pdbx_struct_assembly_gen.asym_id_list / _pdbx_struct_conn_angle.ptnr1_label_asym_id / _pdbx_struct_conn_angle.ptnr2_label_asym_id / _pdbx_struct_conn_angle.ptnr3_label_asym_id / _struct_conn.conn_type_id / _struct_conn.id / _struct_conn.pdbx_dist_value / _struct_conn.pdbx_leaving_atom_flag / _struct_conn.pdbx_role / _struct_conn.ptnr1_auth_asym_id / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr2_auth_asym_id / _struct_conn.ptnr2_auth_comp_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id / _struct_conn.ptnr2_label_atom_id / _struct_conn.ptnr2_label_comp_id / _struct_conn_type.id
Description: Carbohydrate remediation / Provider: repository / Type: Remediation
Revision 3.1Nov 22, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description / Structure summary
Category: chem_comp / chem_comp_atom ...chem_comp / chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / struct_conn
Item: _chem_comp.pdbx_synonyms / _database_2.pdbx_DOI ..._chem_comp.pdbx_synonyms / _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_conn.pdbx_leaving_atom_flag

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Ectonucleotide pyrophosphatase/phosphodiesterase family member 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)99,67229
Polymers96,2121
Non-polymers3,46028
Water4,197233
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2990 Å2
ΔGint-34 kcal/mol
Surface area32020 Å2
MethodPISA
Unit cell
Length a, b, c (Å)61.507, 94.145, 75.556
Angle α, β, γ (deg.)90.000, 93.920, 90.000
Int Tables number4
Space group name H-MP1211

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Components

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Protein , 1 types, 1 molecules A

#1: Protein Ectonucleotide pyrophosphatase/phosphodiesterase family member 2 / E-NPP 2 / Autotaxin / Extracellular lysophospholipase D / LysoPLD


Mass: 96211.977 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Gene: Enpp2, Npps2, Pdnp2 / Production host: Homo sapiens (human)
References: UniProt: Q9R1E6, alkylglycerophosphoethanolamine phosphodiesterase

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Sugars , 2 types, 2 molecules

#2: Polysaccharide alpha-D-mannopyranose-(1-2)-alpha-D-mannopyranose-(1-3)-alpha-D-mannopyranose-(1-6)-alpha-D- ...alpha-D-mannopyranose-(1-2)-alpha-D-mannopyranose-(1-3)-alpha-D-mannopyranose-(1-6)-alpha-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 1072.964 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DManpa1-2DManpa1-3DManpa1-6DManpa1-4DGlcpNAcb1-4DGlcpNAcb1-Glycam Condensed SequenceGMML 1.0
WURCS=2.0/2,6,5/[a2122h-1b_1-5_2*NCC/3=O][a1122h-1a_1-5]/1-1-2-2-2-2/a4-b1_b4-c1_c6-d1_d3-e1_e2-f1WURCSPDB2Glycan 1.1.0
[]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{[(4+1)][a-D-Manp]{[(6+1)][a-D-Manp]{[(3+1)][a-D-Manp]{[(2+1)][a-D-Manp]{}}}}}}}LINUCSPDB-CARE
#3: Polysaccharide alpha-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta- ...alpha-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 586.542 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DManpa1-4DGlcpNAcb1-4DGlcpNAcb1-Glycam Condensed SequenceGMML 1.0
WURCS=2.0/2,3,2/[a2122h-1b_1-5_2*NCC/3=O][a1122h-1a_1-5]/1-1-2/a4-b1_b4-c1WURCSPDB2Glycan 1.1.0
[]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{[(4+1)][a-D-Manp]{}}}}LINUCSPDB-CARE

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Non-polymers , 9 types, 259 molecules

#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-NA / SODIUM ION


Mass: 22.990 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Na
#7: Chemical ChemComp-K / POTASSIUM ION


Mass: 39.098 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: K
#8: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: SO4
#9: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Cl
#10: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 17 / Source method: isolated from a natural source / Formula: C2H6O2
#11: Chemical ChemComp-EAR / ethyl 2-[2-(4-chlorophenyl)-7-methyl-5-oxidanylidene-imidazo[1,2-a]pyrimidin-8-yl]ethanoate


Mass: 345.780 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C17H16ClN3O3 / Feature type: SUBJECT OF INVESTIGATION
#12: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 233 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestY

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

CrystalDensity Matthews: 2.28 Å3/Da / Density % sol: 46.03 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop
Details: 20-25% PEG 3350, 0.15mM NaCl, 0.5M KSCN, 0.2mM ZnSO4, 1% polyvinylpyrrolidone, 0.2mM inhibitor

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SPring-8 / Beamline: BL41XU / Wavelength: 1 Å
DetectorType: RAYONIX MX225HE / Detector: CCD / Date: Apr 22, 2010
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2→47.073 Å / Num. obs: 58034 / % possible obs: 100 % / Redundancy: 7.5 % / Rpim(I) all: 0.042 / Net I/σ(I): 12.4
Reflection shellResolution: 2→2.05 Å / Num. unique obs: 4306 / Rpim(I) all: 0.607

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Processing

Software
NameVersionClassification
PHENIX1.14_3260refinement
XDSdata reduction
Aimlessdata scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3NKM

3nkm


Resolution: 2→47.073 Å / SU ML: 0.27 / Cross valid method: THROUGHOUT / σ(F): 1.35 / Phase error: 25.49 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2368 2807 4.84 %
Rwork0.1894 55198 -
obs0.1917 58005 99.93 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 83.63 Å2 / Biso mean: 41.0223 Å2 / Biso min: 18.21 Å2
Refinement stepCycle: final / Resolution: 2→47.073 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6264 0 215 233 6712
Biso mean--46.81 39.5 -
Num. residues----783
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection Rwork% reflection obs (%)
2.0001-2.03450.38541500.30812717100
2.0345-2.07150.31061570.28592742100
2.0715-2.11140.31341470.26092756100
2.1114-2.15450.30391480.24742760100
2.1545-2.20130.29341330.23932753100
2.2013-2.25250.28221340.232761100
2.2525-2.30890.29731240.22322738100
2.3089-2.37130.2821350.22892783100
2.3713-2.44110.28741280.21812747100
2.4411-2.51990.27871530.21772735100
2.5199-2.60990.2281500.20162758100
2.6099-2.71440.26291520.18922731100
2.7144-2.83790.25061350.19262754100
2.8379-2.98750.26931210.19482770100
2.9875-3.17470.28251260.19722794100
3.1747-3.41970.2111370.18422785100
3.4197-3.76370.23331360.17572771100
3.7637-4.3080.18171380.1572770100
4.308-5.42640.18471400.15352764100
5.4264-470.21771630.1772280999

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