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

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Basic information

Entry
Database: PDB / ID: 5nkf
TitleCrystal Structure of Ephrin A2 (EphA2) Receptor Protein Kinase with Compound 3b
ComponentsEphrin type-A receptor 2
KeywordsTRANSFERASE / Inhibitor / Complex / Protein Tyrosine Kinase
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-8ZN / Ephrin type-A receptor 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.099 Å
AuthorsKudlinzki, D. / Linhard, V.L. / Witt, K. / Gande, S.L. / Saxena, K. / Heinzlmeir, S. / Medard, G. / Kuester, B. / Schwalbe, H.
Funding support Germany, 1items
OrganizationGrant numberCountry
DKTKL590 Germany
CitationJournal: ChemMedChem / Year: 2017
Title: Chemoproteomics-Aided Medicinal Chemistry for the Discovery of EPHA2 Inhibitors.
Authors: Heinzlmeir, S. / Lohse, J. / Treiber, T. / Kudlinzki, D. / Linhard, V. / Gande, S.L. / Sreeramulu, S. / Saxena, K. / Liu, X. / Wilhelm, M. / Schwalbe, H. / Kuster, B. / Medard, G.
History
DepositionMar 31, 2017Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jun 7, 2017Provider: repository / Type: Initial release
Revision 1.1Jun 28, 2017Group: Database references / Category: citation
Item: _citation.country / _citation.journal_volume ..._citation.country / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.title
Revision 1.2Jun 12, 2019Group: Data collection / Structure summary
Category: audit_author / database_PDB_rev / database_PDB_rev_record
Item: _audit_author.name
Revision 1.3Aug 14, 2019Group: Data collection / Category: reflns / reflns_shell
Item: _reflns.pdbx_Rrim_I_all / _reflns_shell.number_unique_obs / _reflns_shell.pdbx_Rrim_I_all
Revision 1.4Jan 17, 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)35,0012
Polymers34,4631
Non-polymers5381
Water5,873326
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration, Monomer
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area14890 Å2
MethodPISA
Unit cell
Length a, b, c (Å)32.716, 107.726, 40.549
Angle α, β, γ (deg.)90.00, 108.65, 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 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P29317, receptor protein-tyrosine kinase
#2: Chemical ChemComp-8ZN / ~{N}-(2-chloranyl-6-methyl-phenyl)-2-[[3-(piperidin-4-ylcarbamoyl)-5-(trifluoromethyl)phenyl]amino]-1,3-thiazole-5-carboxamide


Mass: 537.985 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C24H23ClF3N5O2S
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 326 / 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: 1.96 Å3/Da / Density % sol: 37.39 %
Crystal growTemperature: 291 K / Method: vapor diffusion, sitting drop / pH: 6
Details: 37.5% MPD/PEG1000/PEG3350 (MD), 0.1 M Amino Acids Mix (MD), 0.1 M Bis-Tris pH6.0

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06SA / Wavelength: 0.85506 Å
DetectorType: DECTRIS PILATUS 2M-F / Detector: PIXEL / Date: Feb 7, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.85506 Å / Relative weight: 1
ReflectionResolution: 1.099→38.42 Å / Num. obs: 107443 / % possible obs: 99.7 % / Redundancy: 6.7 % / Biso Wilson estimate: 13.69 Å2 / Rrim(I) all: 0.06 / Net I/σ(I): 18.98
Reflection shellResolution: 1.1→1.17 Å / Mean I/σ(I) obs: 2.4 / Num. unique obs: 10613 / Rrim(I) all: 0.802 / % possible all: 99.1

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Processing

Software
NameVersionClassification
XDSXDSapp 2.0data reduction
Aimlessdata scaling
PHASERphasing
PHENIX(1.10.1_2155: ???)refinement
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5I9U

5i9u


Resolution: 1.099→38.42 Å / SU ML: 0.1 / Cross valid method: FREE R-VALUE / σ(F): 1.37 / Phase error: 18.83
RfactorNum. reflection% reflection
Rfree0.1866 2101 1.96 %
Rwork0.1707 --
obs0.171 107441 99.84 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 1.099→38.42 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2309 0 36 326 2671
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0112601
X-RAY DIFFRACTIONf_angle_d1.4593540
X-RAY DIFFRACTIONf_dihedral_angle_d23.7571042
X-RAY DIFFRACTIONf_chiral_restr0.098376
X-RAY DIFFRACTIONf_plane_restr0.009456
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.0991-1.12470.27941380.26696931X-RAY DIFFRACTION98
1.1247-1.15280.24731390.23446943X-RAY DIFFRACTION100
1.1528-1.1840.24271400.22567020X-RAY DIFFRACTION100
1.184-1.21890.23041400.2147031X-RAY DIFFRACTION100
1.2189-1.25820.20931400.20617051X-RAY DIFFRACTION100
1.2582-1.30320.21581400.19787012X-RAY DIFFRACTION100
1.3032-1.35530.19531410.18697041X-RAY DIFFRACTION100
1.3553-1.4170.20021390.1836985X-RAY DIFFRACTION100
1.417-1.49170.19721410.17087057X-RAY DIFFRACTION100
1.4917-1.58520.17431390.16656984X-RAY DIFFRACTION100
1.5852-1.70760.1581400.16477039X-RAY DIFFRACTION100
1.7076-1.87940.19541410.16097033X-RAY DIFFRACTION100
1.8794-2.15140.16211400.1567050X-RAY DIFFRACTION100
2.1514-2.71040.17451410.1637075X-RAY DIFFRACTION100
2.7104-38.44370.17761420.15147088X-RAY DIFFRACTION100

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