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- PDB-4p5q: Human EphA3 Kinase domain in complex with quinoxaline derivatives -

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Basic information

Entry
Database: PDB / ID: 4p5q
TitleHuman EphA3 Kinase domain in complex with quinoxaline derivatives
ComponentsEphrin type-A receptor 3
KeywordsTRANSFERASE / TRANSFERASE INHIBITOR
Function / homology
Function and homology information


fasciculation of sensory neuron axon / fasciculation of motor neuron axon / transmembrane-ephrin receptor activity / GPI-linked ephrin receptor activity / regulation of epithelial to mesenchymal transition / ephrin receptor activity / negative regulation of endocytosis / EPH-Ephrin signaling / regulation of focal adhesion assembly / regulation of GTPase activity ...fasciculation of sensory neuron axon / fasciculation of motor neuron axon / transmembrane-ephrin receptor activity / GPI-linked ephrin receptor activity / regulation of epithelial to mesenchymal transition / ephrin receptor activity / negative regulation of endocytosis / EPH-Ephrin signaling / regulation of focal adhesion assembly / regulation of GTPase activity / EPHA-mediated growth cone collapse / EPH-ephrin mediated repulsion of cells / ephrin receptor signaling pathway / regulation of microtubule cytoskeleton organization / cellular response to retinoic acid / axon guidance / regulation of actin cytoskeleton organization / positive regulation of protein localization to plasma membrane / receptor protein-tyrosine kinase / positive regulation of neuron projection development / peptidyl-tyrosine phosphorylation / cell migration / actin cytoskeleton / nuclear membrane / early endosome / cell adhesion / dendrite / extracellular region / nucleoplasm / ATP binding / plasma membrane / cytosol
Similarity search - Function
Ephrin type-A receptor 3, 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 ...Ephrin type-A receptor 3, 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 / Growth factor receptor cysteine-rich domain superfamily / EGF-like domain signature 2. / 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 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / 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-Q0B / Ephrin type-A receptor 3
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.35 Å
AuthorsDong, J. / Caflisch, A.
CitationJournal: J.Med.Chem. / Year: 2014
Title: Pyrrolo[3,2-b]quinoxaline Derivatives as Types I1/2 and II Eph Tyrosine Kinase Inhibitors: Structure-Based Design, Synthesis, and in Vivo Validation.
Authors: Unzue, A. / Dong, J. / Lafleur, K. / Zhao, H. / Frugier, E. / Caflisch, A. / Nevado, C.
History
DepositionMar 19, 2014Deposition site: RCSB / Processing site: PDBE
Revision 1.0Aug 13, 2014Provider: repository / Type: Initial release
Revision 1.1Dec 20, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Ephrin type-A receptor 3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)40,8822
Polymers40,4581
Non-polymers4241
Water4,738263
1


  • Idetical with deposited unit
  • defined by software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area13170 Å2
MethodPISA
Unit cell
Length a, b, c (Å)53.374, 38.196, 75.771
Angle α, β, γ (deg.)90.00, 101.61, 90.00
Int Tables number4
Space group name H-MP1211

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Components

#1: Protein Ephrin type-A receptor 3 / EPH-like kinase 4 / hEK4 / HEK / Human embryo kinase / Tyrosine-protein kinase TYRO4 / Tyrosine- ...EPH-like kinase 4 / hEK4 / HEK / Human embryo kinase / Tyrosine-protein kinase TYRO4 / Tyrosine-protein kinase receptor ETK1 / Eph-like tyrosine kinase 1 / EPH receptor A3


Mass: 40458.180 Da / Num. of mol.: 1 / Fragment: Kinase domain, Residues 606-947
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: EPHA3, ETK, ETK1, HEK, TYRO4 / Plasmid: p28-LIC-Thrombin / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3)
References: UniProt: P29320, receptor protein-tyrosine kinase
#2: Chemical ChemComp-Q0B / 2-amino-1-(2-chlorophenyl)-N-(3-ethoxypropyl)-1H-pyrrolo[2,3-b]quinoxaline-3-carboxamide


Mass: 423.895 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C22H22ClN5O2
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 263 / 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: 1.87 Å3/Da / Density % sol: 34.22 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 6.5
Details: 0.1M sodium cacodylate pH 6.5, 0.15M ammonium sulf ate, 22.5% PEG 3350

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06SA / Wavelength: 0.99989 Å
DetectorType: PSI PILATUS 6M / Detector: PIXEL / Date: Feb 22, 2013
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.99989 Å / Relative weight: 1
ReflectionResolution: 1.35→47.48 Å / Num. obs: 64017 / % possible obs: 97.1 % / Redundancy: 4.1 % / Rmerge(I) obs: 0.049 / Rpim(I) all: 0.028 / Net I/σ(I): 15.9 / Num. measured all: 261570
Reflection shell

Diffraction-ID: 1 / Rejects: _

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. measured allNum. unique allRpim(I) all% possible all
1.35-1.3740.7052.11201729980.39893.2
7.39-47.482.90.02734.15902050.01845.3

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Processing

Software
NameVersionClassification
PHENIX(phenix.refine: 1.8.4_1496)refinement
XDSVERSION January 10, 2014 BUILT=20140115data reduction
AimlessVESION: 0.2.17data scaling
PHASER2.5.6phasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2QOB

2qob


Resolution: 1.35→39.189 Å / SU ML: 0.11 / Cross valid method: FREE R-VALUE / σ(F): 1.89 / Phase error: 17.44 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.1819 2000 3.13 %
Rwork0.1572 --
obs0.158 63995 96.69 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 1.35→39.189 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2174 0 30 263 2467
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0052336
X-RAY DIFFRACTIONf_angle_d1.2573171
X-RAY DIFFRACTIONf_dihedral_angle_d14.467880
X-RAY DIFFRACTIONf_chiral_restr0.037344
X-RAY DIFFRACTIONf_plane_restr0.004406
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.3493-1.3830.2691360.24124220X-RAY DIFFRACTION94
1.383-1.42040.21731440.20294445X-RAY DIFFRACTION97
1.4204-1.46220.20451430.17314435X-RAY DIFFRACTION97
1.4622-1.50940.20321430.15784437X-RAY DIFFRACTION97
1.5094-1.56330.20431430.1524429X-RAY DIFFRACTION98
1.5633-1.62590.18761430.14274455X-RAY DIFFRACTION98
1.6259-1.69990.18211460.13554486X-RAY DIFFRACTION98
1.6999-1.78950.15871440.1364498X-RAY DIFFRACTION98
1.7895-1.90170.19911460.14054533X-RAY DIFFRACTION99
1.9017-2.04850.17791460.14024528X-RAY DIFFRACTION99
2.0485-2.25460.17611460.14234529X-RAY DIFFRACTION99
2.2546-2.58080.20531480.15054544X-RAY DIFFRACTION99
2.5808-3.25130.14891480.16044583X-RAY DIFFRACTION99
3.2513-39.20580.17991240.17423873X-RAY DIFFRACTION82

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