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- PDB-5ia1: Crystal Structure of Ephrin A2 (EphA2) Receptor Protein Kinase wi... -

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Basic information

Entry
Database: PDB / ID: 5ia1
TitleCrystal Structure of Ephrin A2 (EphA2) Receptor Protein Kinase with MLN8054
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 / regulation of ERK1 and ERK2 cascade / negative regulation of angiogenesis / osteoclast differentiation / cell chemotaxis / skeletal system development / molecular function activator activity / protein localization to plasma membrane / cell motility / positive regulation of protein localization to plasma membrane / receptor protein-tyrosine kinase / neuron differentiation / ruffle membrane / intrinsic apoptotic signaling pathway in response to DNA damage / osteoblast differentiation / 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-ZZL / Ephrin type-A receptor 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.036 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)35,0023
Polymers34,4631
Non-polymers5392
Water2,450136
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area60 Å2
ΔGint1 kcal/mol
Surface area13020 Å2
MethodPISA
Unit cell
Length a, b, c (Å)32.714, 106.741, 40.729
Angle α, β, γ (deg.)90.00, 108.79, 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-ZZL / 4-{[9-CHLORO-7-(2,6-DIFLUOROPHENYL)-5H-PYRIMIDO[5,4-D][2]BENZAZEPIN-2-YL]AMINO}BENZOIC ACID


Mass: 476.862 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Formula: C25H15ClF2N4O2 / Details: Ligand ID ZZL: MLN8054 / Source: (gene. exp.) Homo sapiens (human) / Cell line (production host): Sf9 / Production host: Spodoptera frugiperda (fall armyworm) / References: receptor protein-tyrosine kinase
#3: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 1
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.: 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: 1.95 Å3/Da / Density % sol: 37.03 %
Crystal growTemperature: 291 K / Method: vapor diffusion, sitting drop
Details: 37.5 % MPD_P1k_P3350, 0.1 M AminoAcidsMix, 0.1 M Bicin pH 7.6

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: PETRA III, EMBL c/o DESY / Beamline: P13 (MX1) / Wavelength: 0.97625 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Sep 17, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97625 Å / Relative weight: 1
ReflectionResolution: 2.036→38.56 Å / Num. obs: 16840 / % possible obs: 99.3 % / Redundancy: 6.79 % / Net I/σ(I): 9.97
Reflection shellResolution: 2.036→2.16 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: 2.036→36.264 Å / SU ML: 0.22 / Cross valid method: FREE R-VALUE / σ(F): 1.38 / Phase error: 23.49
RfactorNum. reflection% reflection
Rfree0.223 842 5 %
Rwork0.1809 --
obs0.183 16836 99.52 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 2.036→36.264 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2081 0 38 136 2255
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0092166
X-RAY DIFFRACTIONf_angle_d1.0942921
X-RAY DIFFRACTIONf_dihedral_angle_d18.9621309
X-RAY DIFFRACTIONf_chiral_restr0.053313
X-RAY DIFFRACTIONf_plane_restr0.005368
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.0356-2.16320.28971370.23272617X-RAY DIFFRACTION99
2.1632-2.33020.26651400.20722657X-RAY DIFFRACTION100
2.3302-2.56460.23521400.19412667X-RAY DIFFRACTION100
2.5646-2.93550.26181420.18062683X-RAY DIFFRACTION100
2.9355-3.69790.21921410.16392677X-RAY DIFFRACTION100
3.6979-36.26980.18481420.17192693X-RAY DIFFRACTION99

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