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- PDB-8c4w: Crystal structure of rat autotaxin and compound MEY-002 -

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Basic information

Entry
Database: PDB / ID: 8c4w
TitleCrystal structure of rat autotaxin and compound MEY-002
ComponentsEctonucleotide pyrophosphatase/phosphodiesterase family member 2
KeywordsHYDROLASE / Inhibitor / co-crystal / ectonucleotide pyrophosphatase/phosphodiesterase (ENPP)
Function / homology
Function and homology information


response to polycyclic arene / alkylglycerophosphoethanolamine phosphodiesterase / sphingolipid catabolic process / phospholipase D / phospholipid catabolic process / phosphatidylcholine catabolic process / phospholipase D activity / positive regulation of lamellipodium morphogenesis / lysophospholipase activity / phosphodiesterase I activity ...response to polycyclic arene / alkylglycerophosphoethanolamine phosphodiesterase / sphingolipid catabolic process / phospholipase D / phospholipid catabolic process / 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 / cellular response to cadmium ion / regulation of cell migration / cell chemotaxis / cellular response to estradiol stimulus / 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
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
7alpha-hydroxycholesterol / IODIDE ION / THIOCYANATE ION / Chem-TIJ / Autotaxin
Similarity search - Component
Biological speciesRattus norvegicus (Norway rat)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.95 Å
AuthorsEymery, M.C. / McCarthy, A.A.
Funding supportEuropean Union, 1items
OrganizationGrant numberCountry
European Molecular Biology Organization (EMBO)European Union
Citation
Journal: Eur.J.Med.Chem. / Year: 2023
Title: Discovery of potent chromone-based autotaxin inhibitors inspired by cannabinoids.
Authors: Eymery, M.C. / Nguyen, K.A. / Basu, S. / Hausmann, J. / Tran-Nguyen, V.K. / Seidel, H.P. / Gutierrez, L. / Boumendjel, A. / McCarthy, A.A.
#1: Journal: Acta Crystallogr D Biol Crystallogr / Year: 2012
Title: Towards automated crystallographic structure refinement with phenix.refine.
Authors: Afonine, P.V. / Grosse-Kunstleve, R.W. / Echols, N. / Headd, J.J. / Moriarty, N.W. / Mustyakimov, M. / Terwilliger, T.C. / Urzhumtsev, A. / Zwart, P.H. / Adams, P.D.
#2: Journal: Acta Crystallogr D Struct Biol / Year: 2019
Title: Macromolecular structure determination using X-rays, neutrons and electrons: recent developments in Phenix.
Authors: Dorothee Liebschner / Pavel V Afonine / Matthew L Baker / Gábor Bunkóczi / Vincent B Chen / Tristan I Croll / Bradley Hintze / Li Wei Hung / Swati Jain / Airlie J McCoy / Nigel W Moriarty ...Authors: Dorothee Liebschner / Pavel V Afonine / Matthew L Baker / Gábor Bunkóczi / Vincent B Chen / Tristan I Croll / Bradley Hintze / Li Wei Hung / Swati Jain / Airlie J McCoy / Nigel W Moriarty / Robert D Oeffner / Billy K Poon / Michael G Prisant / Randy J Read / Jane S Richardson / David C Richardson / Massimo D Sammito / Oleg V Sobolev / Duncan H Stockwell / Thomas C Terwilliger / Alexandre G Urzhumtsev / Lizbeth L Videau / Christopher J Williams / Paul D Adams /
Abstract: Diffraction (X-ray, neutron and electron) and electron cryo-microscopy are powerful methods to determine three-dimensional macromolecular structures, which are required to understand biological ...Diffraction (X-ray, neutron and electron) and electron cryo-microscopy are powerful methods to determine three-dimensional macromolecular structures, which are required to understand biological processes and to develop new therapeutics against diseases. The overall structure-solution workflow is similar for these techniques, but nuances exist because the properties of the reduced experimental data are different. Software tools for structure determination should therefore be tailored for each method. Phenix is a comprehensive software package for macromolecular structure determination that handles data from any of these techniques. Tasks performed with Phenix include data-quality assessment, map improvement, model building, the validation/rebuilding/refinement cycle and deposition. Each tool caters to the type of experimental data. The design of Phenix emphasizes the automation of procedures, where possible, to minimize repetitive and time-consuming manual tasks, while default parameters are chosen to encourage best practice. A graphical user interface provides access to many command-line features of Phenix and streamlines the transition between programs, project tracking and re-running of previous tasks.
History
DepositionJan 5, 2023Deposition site: PDBE / Processing site: PDBE
Revision 1.0Nov 22, 2023Provider: repository / Type: Initial release
Revision 1.1Nov 29, 2023Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.identifier_ORCID / _citation_author.name

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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)102,16525
Polymers98,8261
Non-polymers3,33824
Water5,729318
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4080 Å2
ΔGint-67 kcal/mol
Surface area31470 Å2
Unit cell
Length a, b, c (Å)53.228, 62.863, 70.151
Angle α, β, γ (deg.)98.990, 106.570, 99.510
Int Tables number1
Space group name H-MP1
Space group name HallP1
Symmetry operation#1: x,y,z

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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: 98826.250 Da / Num. of mol.: 1 / Mutation: N410A, N53A
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Rattus norvegicus (Norway rat) / Gene: Enpp2, Atx, Npps2 / Cell line (production host): HEK293 / Production host: Homo sapiens (human)
References: UniProt: Q64610, 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-ROHGlycam 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
[][D-1-deoxy-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{}}LINUCSPDB-CARE

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Non-polymers , 9 types, 341 molecules

#3: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Zn
#4: Chemical
ChemComp-IOD / IODIDE ION


Mass: 126.904 Da / Num. of mol.: 9 / Source method: obtained synthetically / Formula: I
#5: Chemical
ChemComp-SCN / THIOCYANATE ION


Mass: 58.082 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: CNS
#6: Chemical ChemComp-5JK / 7alpha-hydroxycholesterol / (3beta,7alpha,9beta,14beta)-cholest-5-ene-3,7-diol


Mass: 402.653 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C27H46O2
#7: Chemical ChemComp-TIJ / 5,7-bis(oxidanyl)-2-[1-(phenylmethyl)indol-3-yl]chromen-4-one


Mass: 383.396 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C24H17NO4 / Feature type: SUBJECT OF INVESTIGATION
#8: Chemical ChemComp-P6G / HEXAETHYLENE GLYCOL / POLYETHYLENE GLYCOL PEG400


Mass: 282.331 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C12H26O7 / Comment: precipitant*YM
#9: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C3H8O3
#10: Chemical ChemComp-CA / CALCIUM ION


Mass: 40.078 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Ca
#11: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 318 / 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: 2.19 Å3/Da / Density % sol: 43.91 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 7.4
Details: 18-22% (m/v) PEG3350, 0.1-0.3 M NH4I and 0.3 M NaSCN

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID30B / Wavelength: 0.976254 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jan 20, 2021
Details: Be 1D CRL (vertical) and Rh Elliptical mirror (horizontal) focusing
RadiationMonochromator: Si111 channel cut mono / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.976254 Å / Relative weight: 1
ReflectionResolution: 1.945→47.647 Å / Num. obs: 59934 / % possible obs: 97.2 % / Redundancy: 3.3 % / Biso Wilson estimate: 27.75 Å2 / CC1/2: 0.996 / Net I/σ(I): 9.3
Reflection shellResolution: 1.945→1.979 Å / Num. unique obs: 3012 / CC1/2: 0.509

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Processing

Software
NameVersionClassification
PHENIX1.20.1_4487refinement
XDSFeb 5, 2021 (BUILT 20210323)data reduction
Aimless0.7.7data scaling
PHASERPhaser-2.1.2phasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.95→47.647 Å / SU ML: 0.2168 / Cross valid method: FREE R-VALUE / σ(F): 1.98 / Phase error: 24.8585
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2357 2000 3.34 %
Rwork0.1955 57920 -
obs0.1969 59920 97.18 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 38.88 Å2
Refinement stepCycle: LAST / Resolution: 1.95→47.647 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6287 0 147 318 6752
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00836598
X-RAY DIFFRACTIONf_angle_d0.99448940
X-RAY DIFFRACTIONf_chiral_restr0.0578940
X-RAY DIFFRACTIONf_plane_restr0.00871148
X-RAY DIFFRACTIONf_dihedral_angle_d7.3827908
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.95-1.990.30571430.23894128X-RAY DIFFRACTION96.89
1.99-2.050.27011420.22914140X-RAY DIFFRACTION96.77
2.05-2.110.29341430.2214133X-RAY DIFFRACTION97.01
2.11-2.180.23681420.20734090X-RAY DIFFRACTION96.98
2.18-2.250.25191400.2044065X-RAY DIFFRACTION95.16
2.25-2.340.22561440.20244166X-RAY DIFFRACTION97.51
2.34-2.450.26881420.20074104X-RAY DIFFRACTION97.39
2.45-2.580.24111440.19894178X-RAY DIFFRACTION97.76
2.58-2.740.25431440.20054173X-RAY DIFFRACTION97.91
2.74-2.950.23031430.20764134X-RAY DIFFRACTION96.96
2.95-3.250.25261430.20034147X-RAY DIFFRACTION97.74
3.25-3.720.24451440.18734162X-RAY DIFFRACTION97.73
3.72-4.690.20041420.16924140X-RAY DIFFRACTION97.16
4.69-47.6470.2151440.19454160X-RAY DIFFRACTION97.6
Refinement TLS params.Method: refined / Origin x: 22.8369342593 Å / Origin y: -13.004419941 Å / Origin z: -14.9584127898 Å
111213212223313233
T0.00197580255221 Å20.0353054018931 Å2-0.0226047404536 Å2-0.0209710935004 Å2-0.00436252934165 Å2--0.0306088986906 Å2
L0.524293189923 °20.200900038625 °2-0.326514804949 °2-0.42248186768 °20.0203981473648 °2--0.785619609669 °2
S0.0586889955701 Å °-0.00744142453953 Å °-0.0124230810439 Å °0.0190454920229 Å °-0.0223941644953 Å °0.00929179808527 Å °-0.0350076595348 Å °0.0220598339561 Å °0.0189360469454 Å °
Refinement TLS groupSelection details: all

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