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- PDB-4zg6: Structural basis for inhibition of human autotaxin by four novel ... -

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Basic information

Entry
Database: PDB / ID: 4zg6
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 / phospholipase D / phospholipid catabolic process / phosphatidylcholine catabolic process / phospholipase D activity / positive regulation of lamellipodium morphogenesis / phosphodiesterase I activity / phosphatidylcholine lysophospholipase activity ...Vitamin B5 (pantothenate) metabolism / 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 / positive regulation of peptidyl-tyrosine phosphorylation / scavenger receptor activity / alkylglycerophosphoethanolamine phosphodiesterase activity / polysaccharide binding / positive regulation of epithelial cell migration / regulation of cell migration / cell motility / chemotaxis / 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 / Alkaline Phosphatase, subunit A / Alkaline Phosphatase, subunit A / Factor Xa Inhibitor / Somatomedin B domain, chordata / Somatomedin B -like domains / Somatomedin B domain / Somatomedin B-like domain superfamily ...Factor Xa Inhibitor - #20 / Extracellular Endonuclease; Chain A / Extracellular Endonuclease, subunit A / Alkaline Phosphatase, subunit A / Alkaline Phosphatase, subunit A / Factor Xa Inhibitor / 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 / Few Secondary Structures / Irregular / 3-Layer(aba) Sandwich / Alpha Beta
Similarity search - Domain/homology
Chem-4NY / THIOCYANATE ION / Autotaxin
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.8 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 1.2Nov 22, 2017Group: Database references / Derived calculations / Refinement description
Category: citation / pdbx_struct_oper_list / software
Item: _citation.journal_id_CSD / _pdbx_struct_oper_list.symmetry_operation
Revision 2.0Jul 29, 2020Group: Advisory / Atomic model ...Advisory / 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 / pdbx_validate_close_contact / struct_asym / struct_conn / struct_conn_type / 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_asym_id / _atom_site.auth_atom_id / _atom_site.auth_comp_id / _atom_site.auth_seq_id / _atom_site.label_asym_id / _atom_site.label_atom_id / _atom_site.label_comp_id / _atom_site.label_entity_id / _atom_site.type_symbol / _chem_comp.name / _chem_comp.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_validate_close_contact.auth_asym_id_2 / _pdbx_validate_close_contact.auth_seq_id_2 / _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 2.1Sep 27, 2023Group: 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
Revision 2.2Nov 20, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature

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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
B: Ectonucleotide pyrophosphatase/phosphodiesterase family member 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)200,01530
Polymers196,6652
Non-polymers3,35028
Water11,061614
1
A: Ectonucleotide pyrophosphatase/phosphodiesterase family member 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)100,06616
Polymers98,3331
Non-polymers1,73315
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Ectonucleotide pyrophosphatase/phosphodiesterase family member 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)99,94914
Polymers98,3331
Non-polymers1,61713
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)63.616, 70.488, 107.374
Angle α, β, γ (deg.)104.65, 99.27, 99.86
Int Tables number1
Space group name H-MP1

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Components

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Protein / Sugars , 2 types, 4 molecules AB

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


Mass: 98332.578 Da / Num. of mol.: 2 / Fragment: UNP residues 17-863 / Mutation: N411A
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 beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta- ...beta-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.: 2
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DManpb1-4DGlcpNAcb1-4DGlcpNAcb1-Glycam Condensed SequenceGMML 1.0
WURCS=2.0/2,3,2/[a2122h-1b_1-5_2*NCC/3=O][a1122h-1b_1-5]/1-1-2/a4-b1_b4-c1WURCSPDB2Glycan 1.1.0
[]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-Manp]{}}}}LINUCSPDB-CARE

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Non-polymers , 7 types, 640 molecules

#3: Chemical
ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: Zn
#4: Chemical ChemComp-CA / CALCIUM ION


Mass: 40.078 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Ca
#5: Chemical
ChemComp-NA / SODIUM ION


Mass: 22.990 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: Na
#6: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C3H8O3
#7: Chemical ChemComp-4NY / 4-{(Z)-2-[6-chloro-1-(4-fluorobenzyl)-1H-indol-3-yl]-1-cyanoethenyl}benzoic acid


Mass: 430.858 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C25H16ClFN2O2
#8: Chemical
ChemComp-SCN / THIOCYANATE ION


Mass: 58.082 Da / Num. of mol.: 12 / Source method: obtained synthetically / Formula: CNS
#9: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 614 / Source method: isolated from a natural source / Formula: H2O

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Details

Has protein modificationY

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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: 2.42 Å3/Da / Density % sol: 49.2 %
Crystal growTemperature: 298 K / Method: vapor diffusion, sitting drop / Details: 20% PEG 3350, 0.4 M NaSCN

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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-225 / 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: 1.8→50 Å / Num. obs: 154081 / % possible obs: 96.2 % / Redundancy: 2 % / Rmerge(I) obs: 0.057 / Χ2: 1.554 / Net I/av σ(I): 18.981 / Net I/σ(I): 7.3 / Num. measured all: 303694
Reflection shell

Diffraction-ID: 1 / Redundancy: 2 % / Rejects: _

Resolution (Å)Rmerge(I) obsNum. unique allΧ2% possible all
1.8-1.860.664153750.92796
1.86-1.940.499153001.16295.8
1.94-2.030.322154621.09396.4
2.03-2.130.229154481.31596.3
2.13-2.270.159154571.43596.3
2.27-2.440.114154901.47696.9
2.44-2.690.082155041.73196.9
2.69-3.080.059155172.00896.8
3.08-3.880.042153222.37795.6
3.88-500.031152061.99394.9

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassification
REFMAC5.7.0032refinement
DENZOdata reduction
SCALEPACKdata scaling
PHASERphasing
PDB_EXTRACT3.15data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3NKO

3nko


Resolution: 1.8→34.69 Å / Cor.coef. Fo:Fc: 0.968 / Cor.coef. Fo:Fc free: 0.95 / SU B: 3.905 / SU ML: 0.117 / Cross valid method: THROUGHOUT / ESU R: 0.151 / ESU R Free: 0.146 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.265 7754 5 %RANDOM
Rwork0.22039 ---
obs0.22259 146325 96.01 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 37.642 Å2
Baniso -1Baniso -2Baniso -3
1-0 Å2-0 Å2-0.01 Å2
2---0 Å20 Å2
3---0 Å2
Refinement stepCycle: LAST / Resolution: 1.8→34.69 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms11957 0 198 614 12769
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0110.01912587
X-RAY DIFFRACTIONr_bond_other_d0.0010.0211329
X-RAY DIFFRACTIONr_angle_refined_deg1.5081.96517140
X-RAY DIFFRACTIONr_angle_other_deg0.8343.00326050
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.43651526
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.06323.293580
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.581151945
X-RAY DIFFRACTIONr_dihedral_angle_4_deg16.4281579
X-RAY DIFFRACTIONr_chiral_restr0.0870.21836
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.02114164
X-RAY DIFFRACTIONr_gen_planes_other0.0030.022999
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it2.3843.7686068
X-RAY DIFFRACTIONr_mcbond_other2.3813.7656055
X-RAY DIFFRACTIONr_mcangle_it3.3935.637559
X-RAY DIFFRACTIONr_mcangle_other3.3935.637560
X-RAY DIFFRACTIONr_scbond_it2.6273.9186519
X-RAY DIFFRACTIONr_scbond_other2.6213.9156508
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other3.935.7919557
X-RAY DIFFRACTIONr_long_range_B_refined5.730.36614838
X-RAY DIFFRACTIONr_long_range_B_other5.730.36614839
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.802→1.849 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.396 557 -
Rwork0.364 10513 -
obs--93.59 %

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