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- PDB-4zg7: Structural basis for inhibition of human autotaxin by four novel ... -

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Basic information

Entry
Database: PDB / ID: 4zg7
TitleStructural basis for inhibition of human autotaxin by four novel compounds
ComponentsEctonucleotide pyrophosphatase/phosphodiesterase family member 2
KeywordsHydrolase/Hydrolase Inhibitor / Autotaxin / ENPP2 / inhibitor / Hydrolase-Hydrolase Inhibitor complex
Function / homology
Function and homology information


Vitamin B5 (pantothenate) metabolism / alkylglycerophosphoethanolamine phosphodiesterase / sphingolipid catabolic process / phospholipid catabolic process / phosphatidylcholine catabolic process / positive regulation of lamellipodium morphogenesis / lysophospholipase activity / phosphodiesterase I activity / scavenger receptor activity / alkylglycerophosphoethanolamine phosphodiesterase activity ...Vitamin B5 (pantothenate) metabolism / alkylglycerophosphoethanolamine phosphodiesterase / sphingolipid catabolic process / phospholipid catabolic process / phosphatidylcholine catabolic process / positive regulation of lamellipodium morphogenesis / lysophospholipase activity / phosphodiesterase I activity / scavenger receptor activity / alkylglycerophosphoethanolamine phosphodiesterase activity / polysaccharide binding / positive regulation of epithelial cell migration / estrous cycle / regulation of cell migration / cell motility / chemotaxis / positive regulation of peptidyl-tyrosine phosphorylation / nucleic acid binding / hydrolase activity / immune response / calcium ion binding / extracellular space / zinc ion binding / plasma membrane
Similarity search - Function
Factor Xa Inhibitor - #20 / Extracellular Endonuclease; Chain A / 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. ...Factor Xa Inhibitor - #20 / Extracellular Endonuclease; Chain A / 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, subunit A / Alkaline Phosphatase, subunit A / Factor Xa Inhibitor / Alkaline-phosphatase-like, core domain superfamily / Few Secondary Structures / Irregular / 3-Layer(aba) Sandwich / Alpha Beta
Similarity search - Domain/homology
Chem-4O0 / Chem-NKN / Ectonucleotide pyrophosphatase/phosphodiesterase family member 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.75 Å
Model detailsPAT-078
AuthorsStein, A.J. / Bain, G. / Hutchinson, J.H. / Evans, J.F.
CitationJournal: Mol.Pharmacol. / Year: 2015
Title: Structural Basis for Inhibition of Human Autotaxin by Four Potent Compounds with Distinct Modes of Binding.
Authors: Stein, A.J. / Bain, G. / Prodanovich, P. / Santini, A.M. / Darlington, J. / Stelzer, N.M. / Sidhu, R.S. / Schaub, J. / Goulet, L. / Lonergan, D. / Calderon, I. / Evans, J.F. / Hutchinson, J.H.
History
DepositionApr 22, 2015Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 14, 2015Provider: repository / Type: Initial release
Revision 1.1Nov 11, 2015Group: Database references
Revision 2.0Jul 29, 2020Group: Atomic model / Data collection ...Atomic model / Data collection / Database references / Derived calculations / Structure summary
Category: atom_site / chem_comp ...atom_site / chem_comp / citation / 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 / pdbx_struct_oper_list / 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 / _chem_comp.name / _chem_comp.type / _citation.journal_id_CSD / _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_auth_seq_id / _pdbx_struct_conn_angle.ptnr1_label_asym_id / _pdbx_struct_conn_angle.ptnr2_label_asym_id / _pdbx_struct_conn_angle.ptnr3_auth_seq_id / _pdbx_struct_conn_angle.ptnr3_label_asym_id / _pdbx_struct_conn_angle.value / _pdbx_struct_oper_list.symmetry_operation / _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

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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)95,00717
Polymers92,7641
Non-polymers2,24316
Water8,917495
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)61.770, 85.819, 83.855
Angle α, β, γ (deg.)90.000, 111.340, 90.000
Int Tables number4
Space group name H-MP1211

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Components

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Protein / Sugars , 2 types, 2 molecules A

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


Mass: 92764.406 Da / Num. of mol.: 1 / Fragment: UNP residues 55-860
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ENPP2, ATX, PDNP2 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: Q13822, alkylglycerophosphoethanolamine phosphodiesterase
#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.: 1
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

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Non-polymers , 8 types, 510 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-NA / SODIUM ION


Mass: 22.990 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Na
#6: Chemical ChemComp-4O0 / 3-({6-chloro-7-fluoro-2-methyl-1-[2-oxo-2-(spiro[cyclopropane-1,3'-indol]-1'(2'H)-yl)ethyl]-1H-indol-3-yl}sulfanyl)-2-fluorobenzoic acid


Mass: 538.993 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C28H21ClF2N2O3S
#7: Chemical ChemComp-NKN / (2R)-2-hydroxy-3-(phosphonooxy)propyl tetradecanoate / 14:0 LPA, myristoyl lysophosphatidic acid


Mass: 382.429 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C17H35O7P
#8: Chemical
ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 7 / Source method: obtained synthetically / Formula: C3H8O3
#9: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Cl
#10: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 495 / Source method: isolated from a natural source / Formula: H2O

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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: 2.23 Å3/Da / Density % sol: 44.88 %
Crystal growTemperature: 298 K / Method: vapor diffusion, sitting drop / Details: 20% PEG 3350, 0.2 M NaCl

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 21-ID-G / Wavelength: 1 Å
DetectorType: RAYONIX MX-325 / Detector: CCD / Date: Oct 10, 2013
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.75→50 Å / Num. obs: 80774 / % possible obs: 98.9 % / Redundancy: 3.4 % / Rmerge(I) obs: 0.061 / Χ2: 0.738 / Net I/av σ(I): 17.616 / Net I/σ(I): 6.6 / Num. measured all: 276166
Reflection shell

Diffraction-ID: 1 / Redundancy: 3.4 % / Rejects: _

Resolution (Å)Rmerge(I) obsNum. unique allΧ2% possible all
1.75-1.810.49479780.57198.1
1.81-1.890.35779330.60498.1
1.89-1.970.25280000.63198.4
1.97-2.070.1880410.64298.5
2.07-2.20.12880760.66898.7
2.2-2.380.09980540.68299.1
2.38-2.610.08381020.75499.3
2.61-2.990.07481361.07799.5
2.99-3.770.04981641.02999.7
3.77-500.03282900.71199.5

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassification
HKL-2000data collection
SCALEPACKdata scaling
PHASERphasing
REFMACrefinement
PDB_EXTRACT3.15data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.75→37.61 Å / Cor.coef. Fo:Fc: 0.967 / Cor.coef. Fo:Fc free: 0.955 / WRfactor Rfree: 0.1916 / WRfactor Rwork: 0.1605 / FOM work R set: 0.8903 / SU B: 2.19 / SU ML: 0.07 / SU R Cruickshank DPI: 0.1101 / SU Rfree: 0.1046 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.11 / ESU R Free: 0.105 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.1947 4053 5 %RANDOM
Rwork0.1641 ---
obs0.1656 76587 98.47 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 63.29 Å2 / Biso mean: 23.229 Å2 / Biso min: 11.68 Å2
Baniso -1Baniso -2Baniso -3
1--0 Å2-0 Å2-0 Å2
2--0 Å2-0 Å2
3----0 Å2
Refinement stepCycle: final / Resolution: 1.75→37.61 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6195 0 138 495 6828
Biso mean--27.54 29.11 -
Num. residues----776
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.010.0196593
X-RAY DIFFRACTIONr_bond_other_d0.0010.026005
X-RAY DIFFRACTIONr_angle_refined_deg1.4941.9738982
X-RAY DIFFRACTIONr_angle_other_deg0.8333.00413842
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.3685797
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.07723.388307
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.715151041
X-RAY DIFFRACTIONr_dihedral_angle_4_deg15.8891542
X-RAY DIFFRACTIONr_chiral_restr0.0870.2952
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.0217382
X-RAY DIFFRACTIONr_gen_planes_other0.0010.021548
X-RAY DIFFRACTIONr_mcbond_it1.3882.223126
X-RAY DIFFRACTIONr_mcbond_other1.3862.2193124
X-RAY DIFFRACTIONr_mcangle_it2.1313.3223908
LS refinement shellResolution: 1.75→1.797 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.261 270 -
Rwork0.238 5299 -
all-5569 -
obs--92.97 %

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