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- PDB-4p4c: Human EphA3 Kinase domain in complex with quinoxaline derivatives -

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Basic information

Entry
Database: PDB / ID: 4p4c
TitleHuman EphA3 Kinase domain in complex with quinoxaline derivatives
ComponentsEPH receptor A3
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / TRANSFERASE-TRANSFERASE INHIBITOR COMPLEX
Function / homology
Function and homology information


fasciculation of sensory neuron axon / fasciculation of motor neuron axon / ephrin receptor activity / regulation of epithelial to mesenchymal transition / 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 ...fasciculation of sensory neuron axon / fasciculation of motor neuron axon / ephrin receptor activity / regulation of epithelial to mesenchymal transition / 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 / regulation of microtubule cytoskeleton organization / axon guidance / positive regulation of protein localization to plasma membrane / regulation of actin cytoskeleton organization / placental growth factor receptor activity / 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 / receptor protein-tyrosine kinase / peptidyl-tyrosine phosphorylation / positive regulation of neuron projection development / 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 / Fibronectin type III domain / 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-25Q / Ephrin type-A receptor 3 / receptor protein-tyrosine kinase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.599 Å
AuthorsDong, J. / Caflisch, A.
Funding support Switzerland, 2items
OrganizationGrant numberCountry
Krebsliga Switzerland
Swiss National Science Foundation Switzerland
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 12, 2014Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 13, 2014Provider: repository / Type: Initial release
Revision 1.1Oct 1, 2014Group: Database references
Revision 1.2Nov 22, 2017Group: Database references / Derived calculations ...Database references / Derived calculations / Other / Refinement description / Source and taxonomy
Category: citation / entity_src_gen ...citation / entity_src_gen / pdbx_database_status / pdbx_struct_assembly / pdbx_struct_assembly_prop / pdbx_struct_oper_list / software
Item: _citation.journal_id_CSD / _entity_src_gen.pdbx_alt_source_flag ..._citation.journal_id_CSD / _entity_src_gen.pdbx_alt_source_flag / _pdbx_database_status.pdb_format_compatible / _pdbx_struct_assembly.oligomeric_details / _pdbx_struct_assembly_prop.type / _pdbx_struct_assembly_prop.value / _pdbx_struct_oper_list.symmetry_operation / _software.classification
Revision 1.3Sep 27, 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 / refine_hist
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _refine_hist.pdbx_number_atoms_nucleic_acid / _refine_hist.pdbx_number_atoms_protein

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: EPH receptor A3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)40,7922
Polymers40,4581
Non-polymers3331
Water4,936274
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area13240 Å2
MethodPISA
Unit cell
Length a, b, c (Å)53.914, 38.164, 75.527
Angle α, β, γ (deg.)90.000, 101.590, 90.000
Int Tables number4
Space group name H-MP1211
Detailsbiological unit is the same as asym.

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Components

#1: Protein 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 / Plasmid: p28-LIC-Thrombin / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3)
References: UniProt: Q6P4R6, UniProt: P29320*PLUS, receptor protein-tyrosine kinase
#2: Chemical ChemComp-25Q / 2-amino-1-(3-methoxyphenyl)-1H-pyrrolo[2,3-b]quinoxaline-3-carboxamide


Mass: 333.344 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C18H15N5O2
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 274 / 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: 1.88 Å3/Da / Density % sol: 34.62 %
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: 1.599→38.164 Å / Num. all: 39425 / Num. obs: 39425 / % possible obs: 98.2 % / Redundancy: 3.5 % / Biso Wilson estimate: 15.42 Å2 / Rpim(I) all: 0.032 / Rrim(I) all: 0.061 / Rsym value: 0.052 / Net I/av σ(I): 10.378 / Net I/σ(I): 13.9 / Num. measured all: 138288
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
1.599-1.693.50.3172.42022256970.1950.3173.797.6
1.69-1.793.60.2293.22001355000.1390.2295.199.9
1.79-1.913.60.1644.41842851630.10.1646.999.2
1.91-2.063.40.1046.71611546820.0650.10410.597.4
2.06-2.263.40.0719.51455842770.0450.07114.496.4
2.26-2.533.60.05611.71446840360.0340.05617.799.4
2.53-2.923.50.04514.21225735180.0280.04521.798.7
2.92-3.583.40.03417.51020829790.0210.03428.598.3
3.58-5.063.40.02821.8788923270.0170.02835.298.4
5.06-38.1643.30.02920.7413012460.0180.02931.692.5

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Phasing

PhasingMethod: molecular replacement
Phasing MR
Highest resolutionLowest resolution
Rotation2.5 Å33.64 Å
Translation2.5 Å33.64 Å

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Processing

Software
NameVersionClassification
SCALA3.3.16data scaling
XDSdata scaling
PDB_EXTRACT3.14data extraction
PHASERphasing
PHENIX(phenix.refine: 1.8.4_1496)refinement
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2GSF

2gsf


Resolution: 1.599→33.643 Å / FOM work R set: 0.8635 / SU ML: 0.15 / Cross valid method: FREE R-VALUE / σ(F): 0 / Phase error: 20.63 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2017 1964 4.99 %
Rwork0.1781 37386 -
obs0.1793 39350 97.81 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 59.17 Å2 / Biso mean: 18.86 Å2 / Biso min: 5.93 Å2
Refinement stepCycle: final / Resolution: 1.599→33.643 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2110 0 25 274 2409
Biso mean--21.8 28.36 -
Num. residues----266
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0092179
X-RAY DIFFRACTIONf_angle_d1.3432943
X-RAY DIFFRACTIONf_chiral_restr0.05324
X-RAY DIFFRACTIONf_plane_restr0.005369
X-RAY DIFFRACTIONf_dihedral_angle_d14.051819
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 14

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
1.599-1.63880.21351360.20852594273095
1.6388-1.68320.23871260.201126982824100
1.6832-1.73270.23261450.207827242869100
1.7327-1.78860.23811390.195326822821100
1.7886-1.85250.25041350.195827112846100
1.8525-1.92670.2431300.20592599272996
1.9267-2.01440.21781600.18582677283799
2.0144-2.12060.20071210.17922608272995
2.1206-2.25340.2161460.17692622276897
2.2534-2.42730.18821510.17852657280899
2.4273-2.67150.23371350.18452707284298
2.6715-3.05790.1921330.17852715284899
3.0579-3.85170.19141480.16062715286398
3.8517-33.65030.17051590.16372677283695

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