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- PDB-5i9x: Crystal Structure of Ephrin A2 (EphA2) Receptor Protein Kinase wi... -

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Basic information

Entry
Database: PDB / ID: 5i9x
TitleCrystal Structure of Ephrin A2 (EphA2) Receptor Protein Kinase with bosutinib (SKI-606)
ComponentsEphrin type-A receptor 2
KeywordsTRANSFERASE / TYROSINE-PROTEIN KINASE / RECEPTOR / ATP-BINDING
Function / homology
Function and homology information


notochord cell development / notochord formation / lens fiber cell morphogenesis / blood vessel endothelial cell proliferation involved in sprouting angiogenesis / negative regulation of lymphangiogenesis / axial mesoderm formation / pericyte cell differentiation / cAMP metabolic process / positive regulation of bicellular tight junction assembly / regulation of blood vessel endothelial cell migration ...notochord cell development / notochord formation / lens fiber cell morphogenesis / blood vessel endothelial cell proliferation involved in sprouting angiogenesis / negative regulation of lymphangiogenesis / axial mesoderm formation / pericyte cell differentiation / cAMP metabolic process / positive regulation of bicellular tight junction assembly / regulation of blood vessel endothelial cell migration / ephrin receptor activity / leading edge membrane / negative regulation of chemokine production / post-anal tail morphogenesis / bone remodeling / response to growth factor / activation of GTPase activity / tight junction / regulation of lamellipodium assembly / branching involved in mammary gland duct morphogenesis / EPH-Ephrin signaling / neural tube development / RND1 GTPase cycle / RND2 GTPase cycle / RND3 GTPase cycle / mammary gland epithelial cell proliferation / RHOV GTPase cycle / EPHA-mediated growth cone collapse / growth factor binding / regulation of cell adhesion mediated by integrin / lamellipodium membrane / RHOU GTPase cycle / RHOG GTPase cycle / EPH-ephrin mediated repulsion of cells / ephrin receptor signaling pathway / RAC2 GTPase cycle / RAC3 GTPase cycle / vasculogenesis / regulation of angiogenesis / keratinocyte differentiation / RAC1 GTPase cycle / transmembrane receptor protein tyrosine kinase activity / negative regulation of angiogenesis / regulation of ERK1 and ERK2 cascade / osteoclast differentiation / cell chemotaxis / molecular function activator activity / skeletal system development / protein localization to plasma membrane / cell motility / positive regulation of protein localization to plasma membrane / receptor protein-tyrosine kinase / neuron differentiation / ruffle membrane / osteoblast differentiation / intrinsic apoptotic signaling pathway in response to DNA damage / cell migration / lamellipodium / virus receptor activity / receptor complex / cell adhesion / defense response to Gram-positive bacterium / positive regulation of cell migration / inflammatory response / cadherin binding / focal adhesion / cell surface / ATP binding / plasma membrane
Similarity search - Function
Ephrin type-A receptor 2, ligand binding domain / 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. ...Ephrin type-A receptor 2, ligand binding domain / 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 / 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-DB8 / Ephrin type-A receptor 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.427 Å
AuthorsKudlinzki, D. / Linhard, V.L. / Gande, S.L. / Sreeramulu, S. / Saxena, K. / Heinzlmeir, S. / Medard, G. / Kuester, B. / Schwalbe, H.
Funding support Germany, 1items
OrganizationGrant numberCountry
DKTKL590 Germany
CitationJournal: ACS Chem. Biol. / Year: 2016
Title: Chemical Proteomics and Structural Biology Define EPHA2 Inhibition by Clinical Kinase Drugs.
Authors: Heinzlmeir, S. / Kudlinzki, D. / Sreeramulu, S. / Klaeger, S. / Gande, S.L. / Linhard, V. / Wilhelm, M. / Qiao, H. / Helm, D. / Ruprecht, B. / Saxena, K. / Medard, G. / Schwalbe, H. / Kuster, B.
History
DepositionFeb 21, 2016Deposition site: RCSB / Processing site: PDBE
Revision 1.0Nov 9, 2016Provider: repository / Type: Initial release
Revision 1.1Dec 28, 2016Group: Database references
Revision 1.2Mar 7, 2018Group: Data collection / Source and taxonomy / Category: diffrn_source / entity_src_gen
Item: _diffrn_source.pdbx_synchrotron_site / _entity_src_gen.pdbx_host_org_cell_line / _entity_src_gen.pdbx_host_org_strain
Revision 1.3Jun 12, 2019Group: Data collection / Structure summary
Category: audit_author / database_PDB_rev / database_PDB_rev_record
Item: _audit_author.name
Revision 1.4Jan 10, 2024Group: 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 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,2426
Polymers34,4631
Non-polymers7795
Water4,234235
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area730 Å2
ΔGint12 kcal/mol
Surface area14520 Å2
MethodPISA
Unit cell
Length a, b, c (Å)32.803, 107.695, 40.604
Angle α, β, γ (deg.)90.00, 108.95, 90.00
Int Tables number4
Space group name H-MP1211

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Components

#1: Protein Ephrin type-A receptor 2 / Epithelial cell kinase / Tyrosine-protein kinase receptor ECK


Mass: 34462.840 Da / Num. of mol.: 1 / Fragment: UNP residues 596-900
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: EPHA2, ECK / Cell line (production host): SF9 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P29317, receptor protein-tyrosine kinase
#2: Chemical ChemComp-DB8 / 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methylpiperazin-1-yl)propoxy]quinoline-3-carbonitrile / Bosutinib


Mass: 530.446 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Formula: C26H29Cl2N5O3 / Details: Ligand ID DB8: bosutinib / Source: (gene. exp.) Homo sapiens (human) / Cell line (production host): Sf9 / Production host: Spodoptera frugiperda (fall armyworm) / References: receptor protein-tyrosine kinase / Comment: inhibitor, medication*YM
#3: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Formula: C2H6O2 / Details: EDO from cryo soaking / Source: (gene. exp.) Homo sapiens (human) / Cell line (production host): Sf9 / Production host: Spodoptera frugiperda (fall armyworm) / References: receptor protein-tyrosine kinase
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 235 / 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: 1.97 Å3/Da / Density % sol: 37.51 %
Crystal growTemperature: 291 K / Method: vapor diffusion, sitting drop
Details: 37.5 % MPD_P1k_P3350, 0.1 M AminoAcidsMix, 0.1 M MES pH 6.0

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: PETRA III, EMBL c/o DESY / Beamline: P13 (MX1) / Wavelength: 1.0332 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jun 15, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.0332 Å / Relative weight: 1
ReflectionResolution: 1.427→38.402 Å / Num. obs: 94778 / % possible obs: 96.8 % / Redundancy: 3.5 % / Net I/σ(I): 12.09
Reflection shellResolution: 1.427→1.51 Å

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Processing

Software
NameVersionClassification
XDSdata reduction
PHASERphasing
PHENIX(1.10.1_2155: ???)refinement
Cootmodel building
XDSdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1MQB

1mqb


Resolution: 1.427→38.402 Å / SU ML: 0.13 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 17.52
RfactorNum. reflection% reflection
Rfree0.182 4745 5.01 %
Rwork0.165 --
obs0.1659 94776 96.97 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 1.427→38.402 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2268 0 52 235 2555
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0062410
X-RAY DIFFRACTIONf_angle_d0.8773250
X-RAY DIFFRACTIONf_dihedral_angle_d21.065923
X-RAY DIFFRACTIONf_chiral_restr0.082346
X-RAY DIFFRACTIONf_plane_restr0.005410
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.427-1.44320.28711430.27382649X-RAY DIFFRACTION86
1.4432-1.46020.25611510.24742893X-RAY DIFFRACTION95
1.4602-1.4780.26731600.22923026X-RAY DIFFRACTION96
1.478-1.49670.24741560.23612987X-RAY DIFFRACTION96
1.4967-1.51640.2211560.22692955X-RAY DIFFRACTION96
1.5164-1.53720.2751580.21742992X-RAY DIFFRACTION96
1.5372-1.55920.20541550.222978X-RAY DIFFRACTION96
1.5592-1.58240.23271550.20072966X-RAY DIFFRACTION97
1.5824-1.60720.19211560.19722976X-RAY DIFFRACTION97
1.6072-1.63350.18161610.19743030X-RAY DIFFRACTION97
1.6335-1.66170.1691560.19052932X-RAY DIFFRACTION95
1.6617-1.69190.18131550.18632962X-RAY DIFFRACTION97
1.6919-1.72440.21181640.18063049X-RAY DIFFRACTION97
1.7244-1.75960.20951560.17262960X-RAY DIFFRACTION97
1.7596-1.79790.17311580.15863004X-RAY DIFFRACTION97
1.7979-1.83970.1591610.15883063X-RAY DIFFRACTION98
1.8397-1.88570.15561570.15662962X-RAY DIFFRACTION98
1.8857-1.93670.17161630.15273113X-RAY DIFFRACTION98
1.9367-1.99370.1741550.15322958X-RAY DIFFRACTION98
1.9937-2.0580.16221620.15213088X-RAY DIFFRACTION97
2.058-2.13160.19731600.14963044X-RAY DIFFRACTION98
2.1316-2.21690.16151590.153017X-RAY DIFFRACTION99
2.2169-2.31780.19511590.15383053X-RAY DIFFRACTION98
2.3178-2.440.19491590.15493038X-RAY DIFFRACTION99
2.44-2.59280.17171630.15443065X-RAY DIFFRACTION99
2.5928-2.7930.17491610.15943032X-RAY DIFFRACTION98
2.793-3.07390.17991630.15213067X-RAY DIFFRACTION98
3.0739-3.51850.1691570.1483059X-RAY DIFFRACTION99
3.5185-4.43190.1461620.14093059X-RAY DIFFRACTION99
4.4319-38.41610.18471640.1733054X-RAY DIFFRACTION98

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