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- PDB-4p5z: Human EphA3 Kinase domain in complex with quinoxaline derivatives -

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Basic information

Entry
Database: PDB / ID: 4p5z
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 GTPase activity / regulation of focal adhesion assembly ...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 GTPase activity / regulation of focal adhesion assembly / EPHA-mediated growth cone collapse / EPH-ephrin mediated repulsion of cells / ephrin receptor signaling pathway / cellular response to retinoic acid / axon guidance / regulation of microtubule cytoskeleton organization / peptidyl-tyrosine phosphorylation / regulation of actin cytoskeleton organization / positive regulation of protein localization to plasma membrane / positive regulation of neuron projection development / receptor protein-tyrosine kinase / 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 / Fibronectin type III domain / Growth factor receptor cysteine-rich domain superfamily / EGF-like domain signature 2. / 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 / 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-Q7M / Ephrin type-A receptor 3
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.002 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 20, 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 / diffrn_radiation_wavelength / 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)40,9642
Polymers40,4581
Non-polymers5051
Water2,342130
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area12680 Å2
MethodPISA
Unit cell
Length a, b, c (Å)52.805, 38.235, 75.465
Angle α, β, γ (deg.)90.000, 101.460, 90.000
Int Tables number4
Space group name H-MP1211
Detailsbiological unit is the same as asym.

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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
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 BL21(DE3) (bacteria)
References: UniProt: P29320, receptor protein-tyrosine kinase
#2: Chemical ChemComp-Q7M / 2-amino-1-[4-({[3-(trifluoromethyl)phenyl]carbamoyl}amino)phenyl]-1H-pyrrolo[2,3-b]quinoxaline-3-carboxamide


Mass: 505.451 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C25H18F3N7O2
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 130 / 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: 1.85 Å3/Da / Density % sol: 33.35 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 6.5
Details: 0.1M sodium cacodylate pH 6.5, 0.15M ammonium sulfate, 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: 2.002→73.96 Å / Num. all: 20066 / Num. obs: 20066 / % possible obs: 99.1 % / Redundancy: 6.5 % / Biso Wilson estimate: 31.11 Å2 / Rpim(I) all: 0.029 / Rrim(I) all: 0.075 / Rsym value: 0.069 / Net I/av σ(I): 8.114 / Net I/σ(I): 15.6 / Num. measured all: 130503
Reflection shell

Diffraction-ID: 1 / Rejects: _

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. measured allNum. unique allRpim(I) allRsym valueNet I/σ(I) obs% possible all
2-2.116.50.5861.31833428190.2450.586396.2
2.11-2.246.90.36621887627490.1490.3664.799.4
2.24-2.396.60.2542.91699225940.1080.254799.6
2.39-2.586.30.193.81511024160.0830.198.299.7
2.58-2.836.90.1185.91553522490.0490.11813.199.9
2.83-3.176.80.0759.11380820300.0310.07519.599.8
3.17-3.6560.05411.91069617840.0240.05426.799.3
3.65-4.486.20.0415.3945415360.0170.0437.699.7
4.48-6.336.30.03616.3755112030.0150.03641.499.8
6.33-47.01860.02918.241476860.0120.02943.999.1

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Phasing

PhasingMethod: molecular replacement
Phasing MR
Highest resolutionLowest resolution
Rotation2.5 Å47.02 Å
Translation2.5 Å47.02 Å

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Processing

Software
NameVersionClassification
SCALA3.3.20data scaling
PDB_EXTRACT3.14data extraction
PHASERphasing
PHENIX(phenix.refine: 1.8.4_1496)refinement
XDS20140115data reduction
XSCALEdata reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2QOB

2qob


Resolution: 2.002→47.018 Å / FOM work R set: 0.7734 / SU ML: 0.19 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 28.12 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2185 1027 5.13 %
Rwork0.1783 18984 -
obs0.1805 20011 98.76 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 99.36 Å2 / Biso mean: 44.27 Å2 / Biso min: 24.62 Å2
Refinement stepCycle: final / Resolution: 2.002→47.018 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2102 0 55 130 2287
Biso mean--49.11 49.51 -
Num. residues----267
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0142209
X-RAY DIFFRACTIONf_angle_d1.6582986
X-RAY DIFFRACTIONf_chiral_restr0.056327
X-RAY DIFFRACTIONf_plane_restr0.008374
X-RAY DIFFRACTIONf_dihedral_angle_d15.576824
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 7

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
2.0017-2.10730.29541490.26832598274796
2.1073-2.23930.26481490.21312678282799
2.2393-2.41220.24811440.20352690283499
2.4122-2.65490.20741390.174127042843100
2.6549-3.0390.23981380.160127452883100
3.039-3.82860.18451680.16432747291599
3.8286-47.03060.21441400.17182822296299

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