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

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Basic information

Entry
Database: PDB / ID: 5nkd
TitleCrystal Structure of Ephrin A2 (EphA2) Receptor Protein Kinase with Compound 2i
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 / regulation of blood vessel endothelial cell migration / leading edge membrane ...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 / regulation of blood vessel endothelial cell migration / leading edge membrane / negative regulation of chemokine production / post-anal tail morphogenesis / bone remodeling / response to growth factor / positive regulation of bicellular tight junction assembly / activation of GTPase activity / regulation of lamellipodium assembly / branching involved in mammary gland duct morphogenesis / tight junction / 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 / ephrin receptor signaling pathway / EPH-ephrin mediated repulsion of cells / RAC2 GTPase cycle / RAC3 GTPase cycle / regulation of angiogenesis / vasculogenesis / regulation of ERK1 and ERK2 cascade / keratinocyte differentiation / transmembrane receptor protein tyrosine kinase activity / RAC1 GTPase cycle / osteoclast differentiation / negative regulation of angiogenesis / molecular function activator activity / skeletal system development / protein localization to plasma membrane / positive regulation of protein localization to plasma membrane / cell chemotaxis / cell motility / 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 / GPI-linked ephrin receptor activity / transmembrane-ephrin receptor activity / epidermal growth factor receptor activity / fibroblast growth factor receptor activity / insulin-like growth factor receptor activity / receptor protein-tyrosine kinase / neuron differentiation / ruffle membrane / cell surface receptor protein tyrosine kinase signaling pathway / intrinsic apoptotic signaling pathway in response to DNA damage / osteoblast differentiation / cell migration / lamellipodium / virus receptor activity / histone H3Y41 kinase activity / histone H2AXY142 kinase activity / receptor complex / cell adhesion / defense response to Gram-positive bacterium / positive regulation of cell migration / cadherin binding / inflammatory response / 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 / 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-91K / Ephrin type-A receptor 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.408 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 / Item: _reflns.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)35,0243
Polymers34,4631
Non-polymers5612
Water4,161231
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration, Monomer
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1080 Å2
ΔGint0 kcal/mol
Surface area14420 Å2
MethodPISA
Unit cell
Length a, b, c (Å)32.753, 107.477, 40.576
Angle α, β, γ (deg.)90.00, 109.02, 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
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-91K / 2-[(3~{R})-1-[3-[[5-[(2-chloranyl-6-methyl-phenyl)carbamoyl]-1,3-thiazol-2-yl]amino]phenyl]carbonylpyrrolidin-3-yl]ethanoic acid


Mass: 498.982 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C24H23ClN4O4S
#3: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6O2
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 231 / 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: 37.22 %
Crystal growTemperature: 291 K / Method: vapor diffusion, sitting drop / pH: 6.5
Details: 37.5% MPD/PEG1000/PEG3350 (MD), 0.1 M Amino Acids Mix (MD), 0.1 M Hepes pH6.5

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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-F / 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: 1.408→36.129 Å / Num. obs: 48350 / % possible obs: 94.4 % / Redundancy: 5.54 % / Biso Wilson estimate: 18.99 Å2 / Rrim(I) all: 0.103 / Net I/σ(I): 11.11
Reflection shellResolution: 1.408→1.49 Å / Mean I/σ(I) obs: 5.87 / Rrim(I) all: 0.369 / % possible all: 87.6

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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: 1.408→36.129 Å / SU ML: 0.19 / Cross valid method: FREE R-VALUE / σ(F): 1.36 / Phase error: 25.05
RfactorNum. reflection% reflection
Rfree0.224 2100 4.34 %
Rwork0.1843 --
obs0.186 48344 94.53 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 1.408→36.129 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2290 0 38 231 2559
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0132476
X-RAY DIFFRACTIONf_angle_d1.4783351
X-RAY DIFFRACTIONf_dihedral_angle_d20.667978
X-RAY DIFFRACTIONf_chiral_restr0.108355
X-RAY DIFFRACTIONf_plane_restr0.009429
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.4083-1.4410.39781250.35632766X-RAY DIFFRACTION84
1.441-1.47710.3621320.32172910X-RAY DIFFRACTION90
1.4771-1.5170.30521340.30392950X-RAY DIFFRACTION91
1.517-1.56160.29921370.27543019X-RAY DIFFRACTION92
1.5616-1.6120.29871340.26542949X-RAY DIFFRACTION92
1.612-1.66970.33221360.24492984X-RAY DIFFRACTION92
1.6697-1.73650.30161400.23033083X-RAY DIFFRACTION95
1.7365-1.81550.25021410.19063107X-RAY DIFFRACTION95
1.8155-1.91130.22471420.17293141X-RAY DIFFRACTION97
1.9113-2.0310.20111450.16353186X-RAY DIFFRACTION97
2.031-2.18780.21031440.15233178X-RAY DIFFRACTION98
2.1878-2.40790.18251470.15513218X-RAY DIFFRACTION99
2.4079-2.75620.20971470.16153248X-RAY DIFFRACTION99
2.7562-3.47210.17921460.15493215X-RAY DIFFRACTION99
3.4721-36.14090.19311500.15863290X-RAY DIFFRACTION99

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