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- PDB-5ohi: Crystal structure of autotaxin in complex with BI-2545 -

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Basic information

Entry
Database: PDB / ID: 5ohi
TitleCrystal structure of autotaxin in complex with BI-2545
ComponentsEctonucleotide pyrophosphatase/phosphodiesterase family member 2
KeywordsHYDROLASE / PHOSPHOLIPASE / HYDROLASE-HYDROLASE INHIBITOR COMPLEX
Function / homology
Function and homology information


dinucleotide phosphatase activity / alkylglycerophosphoethanolamine phosphodiesterase / sphingolipid catabolic process / phosphatidylcholine catabolic process / positive regulation of lamellipodium morphogenesis / lysophospholipase activity / phosphodiesterase I activity / scavenger receptor activity / alkylglycerophosphoethanolamine phosphodiesterase activity / polysaccharide binding ...dinucleotide phosphatase activity / alkylglycerophosphoethanolamine phosphodiesterase / sphingolipid catabolic process / phosphatidylcholine catabolic process / 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 / calcium ion binding / positive regulation of cell population proliferation / 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-9V8 / : / 3,6,9,12,15-PENTAOXAHEPTADECANE / Ectonucleotide pyrophosphatase/phosphodiesterase family member 2
Similarity search - Component
Biological speciesMus musculus (house mouse)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.66 Å
AuthorsHoerer, S.
CitationJournal: ACS Med Chem Lett / Year: 2017
Title: Discovery of BI-2545: A Novel Autotaxin Inhibitor That Significantly Reduces LPA Levels in Vivo.
Authors: Kuttruff, C.A. / Ferrara, M. / Bretschneider, T. / Hoerer, S. / Handschuh, S. / Nosse, B. / Romig, H. / Nicklin, P. / Roth, G.J.
History
DepositionJul 17, 2017Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jan 3, 2018Provider: repository / Type: Initial release
Revision 2.0Oct 3, 2018Group: Atomic model / Data collection ...Atomic model / Data collection / Derived calculations / Non-polymer description / Structure summary
Category: atom_site / chem_comp ...atom_site / chem_comp / entity / pdbx_entity_nonpoly / pdbx_nonpoly_scheme / pdbx_struct_conn_angle / struct_conn / struct_site / struct_site_gen
Item: _atom_site.B_iso_or_equiv / _atom_site.Cartn_x ..._atom_site.B_iso_or_equiv / _atom_site.Cartn_x / _atom_site.Cartn_y / _atom_site.Cartn_z / _atom_site.auth_atom_id / _atom_site.auth_comp_id / _atom_site.label_atom_id / _atom_site.label_comp_id / _chem_comp.formula / _chem_comp.formula_weight / _chem_comp.id / _chem_comp.mon_nstd_flag / _chem_comp.name / _chem_comp.pdbx_synonyms / _chem_comp.type / _entity.pdbx_description / _pdbx_entity_nonpoly.comp_id / _pdbx_entity_nonpoly.name / _pdbx_nonpoly_scheme.mon_id / _pdbx_nonpoly_scheme.pdb_mon_id / _pdbx_struct_conn_angle.ptnr1_auth_comp_id / _pdbx_struct_conn_angle.ptnr1_label_alt_id / _pdbx_struct_conn_angle.ptnr1_label_atom_id / _pdbx_struct_conn_angle.ptnr1_label_comp_id / _pdbx_struct_conn_angle.ptnr3_auth_comp_id / _pdbx_struct_conn_angle.ptnr3_label_alt_id / _pdbx_struct_conn_angle.ptnr3_label_atom_id / _pdbx_struct_conn_angle.ptnr3_label_comp_id / _pdbx_struct_conn_angle.value / _struct_conn.pdbx_dist_value / _struct_conn.pdbx_ptnr1_label_alt_id / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_site.details / _struct_site.pdbx_auth_comp_id / _struct_site_gen.auth_comp_id / _struct_site_gen.label_comp_id
Revision 3.0Jul 29, 2020Group: Atomic model / Data collection ...Atomic model / Data collection / Derived calculations / Refinement description / Structure summary
Category: atom_site / atom_site_anisotrop ...atom_site / atom_site_anisotrop / 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 / software / struct_asym / struct_conn / 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 / _atom_site_anisotrop.pdbx_auth_asym_id / _atom_site_anisotrop.pdbx_auth_seq_id / _atom_site_anisotrop.pdbx_label_asym_id / _chem_comp.name / _chem_comp.type / _pdbx_struct_assembly_gen.asym_id_list / _pdbx_struct_conn_angle.ptnr1_auth_comp_id / _pdbx_struct_conn_angle.ptnr1_auth_seq_id / _pdbx_struct_conn_angle.ptnr1_label_asym_id / _pdbx_struct_conn_angle.ptnr1_label_atom_id / _pdbx_struct_conn_angle.ptnr1_label_comp_id / _pdbx_struct_conn_angle.ptnr2_label_asym_id / _pdbx_struct_conn_angle.ptnr3_auth_comp_id / _pdbx_struct_conn_angle.ptnr3_auth_seq_id / _pdbx_struct_conn_angle.ptnr3_label_asym_id / _pdbx_struct_conn_angle.ptnr3_label_atom_id / _pdbx_struct_conn_angle.ptnr3_label_comp_id / _pdbx_struct_conn_angle.value / _software.name / _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
Description: Carbohydrate remediation / Provider: repository / Type: Remediation
Revision 3.1Jan 17, 2024Group: Data collection / Database references ...Data collection / Database references / Refinement description / Structure summary
Category: chem_comp / chem_comp_atom ...chem_comp / chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _chem_comp.pdbx_synonyms / _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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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)98,68313
Polymers95,5131
Non-polymers3,17012
Water10,142563
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3760 Å2
ΔGint-8 kcal/mol
Surface area33000 Å2
MethodPISA
Unit cell
Length a, b, c (Å)61.057, 93.779, 75.695
Angle α, β, γ (deg.)90.00, 94.91, 90.00
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: 95513.156 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Gene: Enpp2, Npps2, Pdnp2 / Plasmid: pCDNA5/FRT / Cell line (production host): HEK293 Gnt1 / Production host: Homo sapiens (human)
References: UniProt: Q9R1E6, alkylglycerophosphoethanolamine phosphodiesterase

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Sugars , 2 types, 3 molecules

#2: Polysaccharide 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 424.401 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DGlcpNAcb1-4DGlcpNAcb1-Glycam Condensed SequenceGMML 1.0
WURCS=2.0/1,2,1/[a2122h-1b_1-5_2*NCC/3=O]/1-1/a4-b1WURCSPDB2Glycan 1.1.0
[]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{}}}LINUCSPDB-CARE
#3: 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-(1-3)]beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 1235.105 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DManpa1-2DManpa1-3DManpa1-6[DManpa1-3]DManpb1-4DGlcpNAcb1-4DGlcpNAcb1-Glycam Condensed SequenceGMML 1.0
WURCS=2.0/3,7,6/[a2122h-1b_1-5_2*NCC/3=O][a1122h-1b_1-5][a1122h-1a_1-5]/1-1-2-3-3-3-3/a4-b1_b4-c1_c3-d1_c6-e1_e3-f1_f2-g1WURCSPDB2Glycan 1.1.0
[]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-Manp]{[(3+1)][a-D-Manp]{}[(6+1)][a-D-Manp]{[(3+1)][a-D-Manp]{[(2+1)][a-D-Manp]{}}}}}}}LINUCSPDB-CARE

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Non-polymers , 8 types, 572 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.: 2 / 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-P3G / 3,6,9,12,15-PENTAOXAHEPTADECANE


Mass: 250.332 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C12H26O5
#9: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Cl
#10: Chemical ChemComp-9V8 / [3,5-bis(trifluoromethyl)phenyl]methyl (1~{S},5~{R})-6-[(1~{H}-benzotriazol-5-ylcarbonylamino)methyl]-3-azabicyclo[3.1.0]hexane-3-carboxylate


Mass: 527.419 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C23H19F6N5O3 / Feature type: SUBJECT OF INVESTIGATION
#11: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 563 / Source method: isolated from a natural source / Formula: H2O

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Details

Sequence detailsPROTEIN USED IN THIS STRUCTURE IS AN ISOFORM OF ANTOTAXIN FROM MOUSE, WHICH IS LACK OF RESIDUES ...PROTEIN USED IN THIS STRUCTURE IS AN ISOFORM OF ANTOTAXIN FROM MOUSE, WHICH IS LACK OF RESIDUES KVEP (UNP RESDIUES 571-574 OF DATABASE ENPP2_MOUSE).

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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: 2.41 Å3/Da / Density % sol: 48.9 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 8
Details: 1 %w/v Polyvinylpyrolidine (PVP K15)21 %w/v Polyethylene glycol 3,350, 0.2 M ZnSO4, 0.5 M KSCN and 0.1 M BIS-TRIS at pH8.0

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X10SA / Wavelength: 0.90996 Å
DetectorType: DECTRIS PILATUS 6M-F / Detector: PIXEL / Date: Apr 12, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.90996 Å / Relative weight: 1
ReflectionResolution: 1.66→75.417 Å / Num. obs: 98475 / % possible obs: 69.1 % / Redundancy: 3.5 % / Biso Wilson estimate: 28.08 Å2 / CC1/2: 0.998 / Rmerge(I) obs: 0.064 / Rpim(I) all: 0.04 / Rsym value: 0.076 / Net I/σ(I): 11.3
Reflection shellResolution: 1.662→1.722 Å / Redundancy: 3.3 % / Rmerge(I) obs: 3.334 / Mean I/σ(I) obs: 0.39 / Num. unique obs: 188 / CC1/2: 0.0794 / Rpim(I) all: 2.18 / Rsym value: 3.995 / % possible all: 2

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Processing

Software
NameVersionClassification
autoPROC1.1.7data collection
XDSMay 1 2016data reduction
autoPROC1.1.7data scaling
Aimless0.5.31data scaling
BUSTER2.11.7refinement
PHASER2.5.7phasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3NKM

3nkm


Resolution: 1.66→39.82 Å / Cor.coef. Fo:Fc: 0.962 / Cor.coef. Fo:Fc free: 0.948 / SU R Cruickshank DPI: 0.133 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.137 / SU Rfree Blow DPI: 0.118 / SU Rfree Cruickshank DPI: 0.117
RfactorNum. reflection% reflectionSelection details
Rfree0.2 3319 4.81 %RANDOM
Rwork0.17 ---
obs0.171 68935 68.8 %-
Displacement parametersBiso mean: 39.56 Å2
Baniso -1Baniso -2Baniso -3
1--0.4203 Å20 Å2-0.2531 Å2
2--1.6795 Å20 Å2
3----1.2592 Å2
Refine analyzeLuzzati coordinate error obs: 0.22 Å
Refinement stepCycle: LAST / Resolution: 1.66→39.82 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6299 0 200 563 7062
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0086760HARMONIC2
X-RAY DIFFRACTIONt_angle_deg0.969206HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d2356SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes153HARMONIC2
X-RAY DIFFRACTIONt_gen_planes964HARMONIC5
X-RAY DIFFRACTIONt_it6760HARMONIC20
X-RAY DIFFRACTIONt_nbd0SEMIHARMONIC5
X-RAY DIFFRACTIONt_omega_torsion3.38
X-RAY DIFFRACTIONt_other_torsion16.02
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion874SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact8185SEMIHARMONIC4
LS refinement shellResolution: 1.66→1.7 Å
RfactorNum. reflection% reflection
Rfree0.34 11 8.33 %
Rwork0.3176 188 -
obs--1.89 %
Refinement TLS params.Method: refined / Origin x: 17.2298 Å / Origin y: -23.1583 Å / Origin z: 35.6996 Å
111213212223313233
T-0.139 Å20.0078 Å2-0.0207 Å2--0.1415 Å2-0.0074 Å2---0.1355 Å2
L1.0749 °20.334 °2-0.2052 °2-0.6942 °2-0.0408 °2--1.0349 °2
S-0.0834 Å °0.031 Å °-0.014 Å °-0.1099 Å °0.0554 Å °0.0463 Å °0.0419 Å °0.0171 Å °0.028 Å °
Refinement TLS groupSelection details: { A|* }

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