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- PDB-8c3o: Crystal structure of autotaxin gamma and compound MEY-003 -

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Basic information

Entry
Database: PDB / ID: 8c3o
TitleCrystal structure of autotaxin gamma and compound MEY-003
ComponentsEctonucleotide pyrophosphatase/phosphodiesterase family member 2
KeywordsHYDROLASE / Inhibitor / co-crystal / ectonucleotide pyrophosphatase/phosphodiesterase (ENPP)
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
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 / Chem-T8R / Ectonucleotide pyrophosphatase/phosphodiesterase family member 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.47 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
DepositionDec 27, 2022Deposition 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
B: Ectonucleotide pyrophosphatase/phosphodiesterase family member 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)212,08956
Polymers204,0482
Non-polymers8,04154
Water88349
1
A: Ectonucleotide pyrophosphatase/phosphodiesterase family member 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)106,58132
Polymers102,0241
Non-polymers4,55731
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Ectonucleotide pyrophosphatase/phosphodiesterase family member 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)105,50824
Polymers102,0241
Non-polymers3,48423
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)53.925, 288.478, 57.643
Angle α, β, γ (deg.)90.000, 90.120, 90.000
Int Tables number4
Space group name H-MP1211
Space group name HallP2yb
Symmetry operation#1: x,y,z
#2: -x,y+1/2,-z

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Components

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Protein , 1 types, 2 molecules AB

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


Mass: 102023.867 Da / Num. of mol.: 2 / Mutation: N54A, N411A
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ENPP2, ATX, PDNP2 / Plasmid: pcDNA5.1 / Cell line (production host): HEK293 / Organ (production host): Kidney / Production host: Homo sapiens (human)
References: UniProt: Q13822, alkylglycerophosphoethanolamine phosphodiesterase

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Sugars , 2 types, 2 molecules

#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.: 1
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DManpb1-4DGlcpNAcb1-4DGlcpNAcb1-ROHGlycam 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
[][D-1-deoxy-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-Manp]{}}}LINUCSPDB-CARE
#3: 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 , 7 types, 101 molecules

#4: Chemical ChemComp-5JK / 7alpha-hydroxycholesterol / (3beta,7alpha,9beta,14beta)-cholest-5-ene-3,7-diol


Mass: 402.653 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C27H46O2
#5: Chemical ChemComp-T8R / 5,7-bis(oxidanyl)-2-(1-pentylindol-3-yl)chromen-4-one


Mass: 363.406 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C22H21NO4 / Feature type: SUBJECT OF INVESTIGATION
#6: Chemical
ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: C3H8O3
#7: Chemical
ChemComp-ZN / ZINC ION


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


Mass: 126.904 Da / Num. of mol.: 37 / Source method: obtained synthetically / Formula: I
#9: Chemical ChemComp-CA / CALCIUM ION


Mass: 40.078 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Ca
#10: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 49 / 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: 2.35 Å3/Da / Density % sol: 47.72 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 8
Details: 18-22% PEG3350, 0,1-0,4M Ammonium Iodide, 0,1-0.4M Sodium Thiocyanate

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID30B / Wavelength: 0.97625 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: May 4, 2022
RadiationMonochromator: Si111 channel cut mono / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97625 Å / Relative weight: 1
ReflectionResolution: 2.468→144.239 Å / Num. obs: 45039 / % possible obs: 98.9 % / Redundancy: 3.3 % / Biso Wilson estimate: 25.67 Å2 / CC1/2: 0.964 / Net I/σ(I): 3.6
Reflection shellResolution: 2.468→2.758 Å / Num. unique obs: 2191 / CC1/2: 0.52

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Processing

Software
NameVersionClassification
PHENIX1.20.1_4487refinement
autoPROC1.1.7data processing
Aimless0.7.7data scaling
pointless1.12.12data scaling
XDSJan 10, 2022 (BUILT 20220110)data reduction
STARANISO2.3.79 (20211010)data scaling
PHASER2.1.2phasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4ZG6

4zg6


Resolution: 2.47→57.64 Å / SU ML: 0.2825 / Cross valid method: FREE R-VALUE / σ(F): 1.36 / Phase error: 28.436
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2711 2186 4.99 %
Rwork0.2139 41644 -
obs0.2166 43830 69.72 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 28.34 Å2
Refinement stepCycle: LAST / Resolution: 2.47→57.64 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms12637 0 252 49 12938
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.002213319
X-RAY DIFFRACTIONf_angle_d0.521118095
X-RAY DIFFRACTIONf_chiral_restr0.04061921
X-RAY DIFFRACTIONf_plane_restr0.00432317
X-RAY DIFFRACTIONf_dihedral_angle_d6.68121847
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.47-2.520.455530.384247X-RAY DIFFRACTION1.29
2.52-2.580.302440.2991100X-RAY DIFFRACTION2.74
2.58-2.640.4788140.2969233X-RAY DIFFRACTION6.29
2.64-2.720.3495580.2812899X-RAY DIFFRACTION24.26
2.72-2.80.2934630.28151642X-RAY DIFFRACTION44.06
2.8-2.890.30141310.27422261X-RAY DIFFRACTION60.99
2.89-2.990.32831800.28213049X-RAY DIFFRACTION81.87
2.99-3.110.3231850.26653528X-RAY DIFFRACTION95.33
3.11-3.250.29571880.26233718X-RAY DIFFRACTION99.54
3.25-3.420.26032250.23283751X-RAY DIFFRACTION99.9
3.42-3.640.26941740.21123731X-RAY DIFFRACTION99.9
3.64-3.920.28221810.19533741X-RAY DIFFRACTION99.77
3.92-4.310.27971970.17083708X-RAY DIFFRACTION99.9
4.31-4.930.1971810.15783802X-RAY DIFFRACTION100
4.93-6.220.26091790.19613713X-RAY DIFFRACTION99.51
6.22-57.640.2462230.2173721X-RAY DIFFRACTION99.25
Refinement TLS params.Method: refined / Origin x: 16.3361149245 Å / Origin y: -50.7255025913 Å / Origin z: 41.0752972265 Å
111213212223313233
T0.160085542577 Å2-0.0237270926096 Å2-0.0209291857027 Å2-0.169160560868 Å2-0.0257472862823 Å2--0.123651810898 Å2
L0.0866326060181 °2-0.0414231356873 °2-0.0397268788237 °2-0.222415518876 °2-0.141380255132 °2--0.0909538148661 °2
S-0.0029990785033 Å °0.0119241629058 Å °-0.0006053192805 Å °-0.00191428788525 Å °-0.00750604574967 Å °-0.00429906371742 Å °0.00155128276945 Å °0.00328566475083 Å °0.0127838265742 Å °
Refinement TLS groupSelection details: all

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