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- PDB-2xyu: Crystal structure of EphA4 kinase domain in complex with VUF 12058 -

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Basic information

Entry
Database: PDB / ID: 2xyu
TitleCrystal structure of EphA4 kinase domain in complex with VUF 12058
ComponentsEPHRIN TYPE-A RECEPTOR 4,
KeywordsTRANSFERASE / SIGNALING PROTEIN
Function / homology
Function and homology information


EPH-Ephrin signaling / DH domain binding / neuron projection fasciculation / : / EPHA-mediated growth cone collapse / negative regulation of proteolysis involved in protein catabolic process / corticospinal tract morphogenesis / EPH-ephrin mediated repulsion of cells / regulation of astrocyte differentiation / neuron projection guidance ...EPH-Ephrin signaling / DH domain binding / neuron projection fasciculation / : / EPHA-mediated growth cone collapse / negative regulation of proteolysis involved in protein catabolic process / corticospinal tract morphogenesis / EPH-ephrin mediated repulsion of cells / regulation of astrocyte differentiation / neuron projection guidance / nephric duct morphogenesis / fasciculation of sensory neuron axon / fasciculation of motor neuron axon / synapse pruning / negative regulation of cellular response to hypoxia / negative regulation of axon regeneration / glial cell migration / PH domain binding / regulation of modification of synaptic structure / regulation of synapse pruning / regulation of dendritic spine morphogenesis / positive regulation of dendrite morphogenesis / negative regulation of cell adhesion / innervation / adherens junction organization / motor neuron axon guidance / adult walking behavior / regulation of GTPase activity / negative regulation of epithelial to mesenchymal transition / positive regulation of amyloid-beta formation / regulation of axonogenesis / cochlea development / positive regulation of intracellular signal transduction / negative regulation of long-term synaptic potentiation / positive regulation of JUN kinase activity / ephrin receptor signaling pathway / axonal growth cone / axon terminus / ephrin receptor binding / transmembrane receptor protein tyrosine kinase activity / positive regulation of cell adhesion / axon guidance / dendritic shaft / negative regulation of cell migration / protein tyrosine kinase binding / filopodium / adherens junction / placental growth factor receptor activity / postsynaptic density membrane / insulin receptor activity / vascular endothelial growth factor receptor activity / hepatocyte growth factor receptor activity / macrophage colony-stimulating factor receptor activity / platelet-derived growth factor alpha-receptor activity / platelet-derived growth factor beta-receptor activity / stem cell factor receptor activity / boss receptor activity / protein tyrosine kinase collagen receptor activity / brain-derived neurotrophic factor receptor activity / transmembrane-ephrin receptor activity / GPI-linked ephrin receptor activity / epidermal growth factor receptor activity / fibroblast growth factor receptor activity / insulin-like growth factor receptor activity / negative regulation of ERK1 and ERK2 cascade / receptor protein-tyrosine kinase / neuromuscular junction / peptidyl-tyrosine phosphorylation / Schaffer collateral - CA1 synapse / cellular response to amyloid-beta / presynaptic membrane / negative regulation of neuron projection development / protein autophosphorylation / early endosome membrane / dendritic spine / perikaryon / negative regulation of neuron apoptotic process / mitochondrial outer membrane / postsynaptic membrane / protein kinase activity / cell adhesion / protein stabilization / positive regulation of cell migration / axon / positive regulation of cell population proliferation / dendrite / glutamatergic synapse / cell surface / ATP binding / identical protein binding / plasma membrane / cytoplasm
Similarity search - Function
Ephrin type-A receptor 4, SAM domain / Ephrin type-A receptor 4, ligand binding domain / Tyrosine-protein kinase ephrin type A/B receptor-like / Tyrosine-protein kinase ephrin type A/B receptor-like / Ephrin receptor type-A /type-B / Ephrin receptor ligand binding domain / Tyrosine-protein kinase, receptor class V, conserved site / Ephrin receptor, transmembrane domain / : / Ephrin receptor ligand binding domain ...Ephrin type-A receptor 4, SAM domain / Ephrin type-A receptor 4, ligand binding domain / Tyrosine-protein kinase ephrin type A/B receptor-like / Tyrosine-protein kinase ephrin type A/B receptor-like / Ephrin receptor type-A /type-B / Ephrin receptor ligand binding domain / Tyrosine-protein kinase, receptor class V, conserved site / Ephrin receptor, transmembrane domain / : / Ephrin receptor ligand binding domain / Ephrin type-A receptor 2 transmembrane domain / Receptor tyrosine kinase class V signature 1. / Receptor tyrosine kinase class V signature 2. / Eph receptor ligand-binding domain profile. / Ephrin receptor ligand binding domain / Putative ephrin-receptor like / SAM domain (Sterile alpha motif) / SAM domain profile. / Sterile alpha motif. / Sterile alpha motif domain / Sterile alpha motif/pointed domain superfamily / Fibronectin type III domain / Fibronectin type 3 domain / Fibronectin type-III domain profile. / Galactose-binding-like domain superfamily / Fibronectin type III / Fibronectin type III superfamily / Tyrosine-protein kinase, catalytic domain / Tyrosine kinase, catalytic domain / Tyrosine protein kinases specific active-site signature. / Tyrosine-protein kinase, active site / Serine-threonine/tyrosine-protein kinase, catalytic domain / Protein tyrosine and serine/threonine kinase / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Serine/Threonine protein kinases, catalytic domain / Protein kinase, ATP binding site / Protein kinases ATP-binding region signature. / Immunoglobulin-like fold / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily / 2-Layer Sandwich / Orthogonal Bundle / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
Chem-Q9G / Ephrin type-A receptor 4
Similarity search - Component
Biological speciesMUS MUSCULUS (house mouse)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.117 Å
AuthorsFarenc, C.J.A. / Celie, P.H.N. / vanLinden, O.P.J. / Siegal, G.
CitationJournal: Eur.J.Med.Chem. / Year: 2012
Title: Fragment Based Lead Discovery of Small Molecule Inhibitors for the Epha4 Receptor Tyrosine Kinase.
Authors: Van Linden, O.P. / Farenc, C.J.A. / Zoutman, W.H. / Hameetman, L. / Wijtmans, M. / Leurs, R. / Tensen, C.P. / Siegal, G. / De Esch, I.J.
History
DepositionNov 19, 2010Deposition site: PDBE / Processing site: PDBE
Revision 1.0Nov 30, 2011Provider: repository / Type: Initial release
Revision 1.1Dec 28, 2011Group: Other
Revision 1.2Jan 25, 2012Group: Other
Revision 1.3Feb 1, 2012Group: Other
Revision 1.4Dec 20, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Other / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_database_status / pdbx_initial_refinement_model / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_database_status.status_code_sf / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: EPHRIN TYPE-A RECEPTOR 4,
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,0818
Polymers32,2321
Non-polymers8497
Water2,450136
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)32.544, 91.545, 97.959
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

#1: Protein EPHRIN TYPE-A RECEPTOR 4, / EPHA4 / TYROSINE-PROTEIN KINASE RECEPTOR MPK-3 / TYROSINE-PROTEIN KINASE RECEPTOR SEK-1


Mass: 32232.320 Da / Num. of mol.: 1 / Fragment: KINASE DOMAIN, RESIDUES 1548-1832
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) MUS MUSCULUS (house mouse) / Plasmid: PET28AKDONLY / Production host: ESCHERICHIA COLI (E. coli) / Strain (production host): BL21(DE3)
References: UniProt: Q03137, receptor protein-tyrosine kinase
#2: Chemical
ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: C3H8O3
#3: Chemical ChemComp-Q9G / 5-(5-FLUORO-2-METHYLPHENYL)-6,7,8,9-TETRAHYDRO-3H-PYRAZOLO[3,4-C]ISOQUINOLIN-1-AMINE


Mass: 296.342 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C17H17FN4
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 136 / 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: 2.27 Å3/Da / Density % sol: 45.77 % / Description: NONE
Crystal growpH: 5.5 / Details: AMMONIUM SULFATE, BISTRIS PH 5.5, PEG 10K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID23-2 / Wavelength: 0.8726
DetectorType: MARMOSAIC 225 mm CCD / Detector: CCD / Date: Aug 29, 2010 / Details: MIRROR
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.8726 Å / Relative weight: 1
ReflectionResolution: 2.12→43.19 Å / Num. obs: 17378 / % possible obs: 99.5 % / Observed criterion σ(I): 6 / Redundancy: 3.6 % / Biso Wilson estimate: 20.96 Å2 / Rmerge(I) obs: 0.14 / Net I/σ(I): 8.5
Reflection shellResolution: 2.12→2.23 Å / Redundancy: 3.6 % / Rmerge(I) obs: 0.69 / Mean I/σ(I) obs: 1.9 / % possible all: 98.2

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Processing

Software
NameVersionClassification
PHENIX(PHENIX.REFINE)refinement
XDSdata reduction
XDSdata scaling
AMoREphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 2Y6M

2y6m


Resolution: 2.117→43.187 Å / SU ML: 0.23 / σ(F): 0 / Phase error: 21.64 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2298 822 5.1 %
Rwork0.1894 --
obs0.1916 16232 93.16 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL / Bsol: 60.011 Å2 / ksol: 0.4 e/Å3
Displacement parameters
Baniso -1Baniso -2Baniso -3
1--1.3133 Å20 Å20 Å2
2---2.233 Å20 Å2
3---3.5463 Å2
Refinement stepCycle: LAST / Resolution: 2.117→43.187 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2030 0 58 136 2224
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0092127
X-RAY DIFFRACTIONf_angle_d1.0242862
X-RAY DIFFRACTIONf_dihedral_angle_d12.211789
X-RAY DIFFRACTIONf_chiral_restr0.068309
X-RAY DIFFRACTIONf_plane_restr0.004355
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.1168-2.24940.32491060.25892301X-RAY DIFFRACTION85
2.2494-2.42310.28021320.21912426X-RAY DIFFRACTION90
2.4231-2.66690.2371230.19142550X-RAY DIFFRACTION93
2.6669-3.05270.23541350.17532600X-RAY DIFFRACTION95
3.0527-3.84570.1821600.1562689X-RAY DIFFRACTION98
3.8457-43.19570.23011660.19342844X-RAY DIFFRACTION98

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