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

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Basic information

Entry
Database: PDB / ID: 5nkc
TitleCrystal Structure of Ephrin A2 (EphA2) Receptor Protein Kinase with Compound 2h
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 / 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 / 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 / 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-90T / Ephrin type-A receptor 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.448 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 1.2May 2, 2018Group: Data collection / Structure summary / Category: audit_author / reflns / Item: _audit_author.name / _reflns.pdbx_Rpim_I_all
Revision 1.3Aug 14, 2019Group: Data collection / Category: reflns / Item: _reflns.pdbx_Rpim_I_all / _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)35,0103
Polymers34,4631
Non-polymers5472
Water4,342241
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration, Monomer
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area950 Å2
ΔGint-1 kcal/mol
Surface area14630 Å2
MethodPISA
Unit cell
Length a, b, c (Å)32.778, 107.801, 40.597
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-90T / (3~{S})-1-[3-[[5-[(2-chloranyl-6-methyl-phenyl)carbamoyl]-1,3-thiazol-2-yl]amino]phenyl]carbonylpyrrolidine-3-carboxylic acid


Mass: 484.955 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C23H21ClN4O4S
#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.: 241 / 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: 37.49 %
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 MES pH6.0

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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-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: 1.45→38.382 Å / Num. obs: 46248 / % possible obs: 97.6 % / Redundancy: 6.82 % / Biso Wilson estimate: 19.64 Å2 / Rrim(I) all: 0.101 / Net I/σ(I): 15.31
Reflection shellResolution: 1.45→1.54 Å / Mean I/σ(I) obs: 2.47 / Rrim(I) all: 0.78 / % possible all: 95.5

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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: 1.448→38.382 Å / SU ML: 0.14 / Cross valid method: FREE R-VALUE / σ(F): 1.38 / Phase error: 18.23
RfactorNum. reflection% reflection
Rfree0.191 2101 4.54 %
Rwork0.1602 --
obs0.1616 46245 97.76 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 1.448→38.382 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2290 0 37 241 2568
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0122479
X-RAY DIFFRACTIONf_angle_d1.4083356
X-RAY DIFFRACTIONf_dihedral_angle_d20.66985
X-RAY DIFFRACTIONf_chiral_restr0.101355
X-RAY DIFFRACTIONf_plane_restr0.008430
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.4476-1.48120.25651350.22272831X-RAY DIFFRACTION93
1.4812-1.51830.23221360.2042863X-RAY DIFFRACTION97
1.5183-1.55930.21531390.19932923X-RAY DIFFRACTION96
1.5593-1.60520.22741390.18942906X-RAY DIFFRACTION98
1.6052-1.6570.26091380.19242915X-RAY DIFFRACTION96
1.657-1.71630.21041400.18712945X-RAY DIFFRACTION98
1.7163-1.7850.19931390.16182907X-RAY DIFFRACTION98
1.785-1.86620.17971400.15472942X-RAY DIFFRACTION98
1.8662-1.96460.17381400.15122959X-RAY DIFFRACTION98
1.9646-2.08770.17531400.1452936X-RAY DIFFRACTION98
2.0877-2.24880.16851430.14093011X-RAY DIFFRACTION99
2.2488-2.47510.17161410.14692966X-RAY DIFFRACTION99
2.4751-2.83320.18951440.1543012X-RAY DIFFRACTION99
2.8332-3.56910.18551420.14862994X-RAY DIFFRACTION99
3.5691-38.3950.18941450.16283034X-RAY DIFFRACTION99

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