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- PDB-6hew: Crystal Structure of Ephrin A2 (EphA2) Receptor Protein Kinase wi... -

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Basic information

Entry
Database: PDB / ID: 6hew
TitleCrystal Structure of Ephrin A2 (EphA2) Receptor Protein Kinase with the NVP-BHG712 derivative AT069
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 / negative regulation of chemokine production / ephrin receptor activity / leading edge membrane / bone remodeling / post-anal tail morphogenesis / response to growth factor / activation of GTPase activity / regulation of lamellipodium assembly / tight junction / 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 / negative regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / 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 / cell chemotaxis / negative regulation of angiogenesis / osteoclast differentiation / regulation of ERK1 and ERK2 cascade / phosphatidylinositol 3-kinase/protein kinase B signal transduction / skeletal system development / molecular function activator activity / cell motility / protein localization to plasma membrane / positive regulation of protein localization to plasma membrane / receptor protein-tyrosine kinase / neuron differentiation / ruffle membrane / osteoblast differentiation / cell surface receptor protein tyrosine kinase signaling pathway / intrinsic apoptotic signaling pathway in response to DNA damage / cell migration / virus receptor activity / lamellipodium / receptor complex / cell adhesion / positive regulation of cell migration / defense response to Gram-positive bacterium / cadherin binding / inflammatory response / phosphorylation / 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. / Eph receptor ligand-binding domain profile. ...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 / Protein tyrosine and serine/threonine kinase / Serine-threonine/tyrosine-protein kinase, catalytic domain / 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-G0E / Ephrin type-A receptor 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.268 Å
AuthorsKudlinzki, D. / Troester, A. / Witt, K. / Linhard, V.L. / Gande, S.L. / Saxena, K. / Schwalbe, H.
CitationJournal: To Be Published
Title: Effects of NVP-BHG712 chemical modifications on EPHA2 binding and affinity
Authors: Troester, A. / Kudlinzki, D. / Saxena, K. / Gande, S. / Schwalbe, H.
History
DepositionAug 20, 2018Deposition site: PDBE / Processing site: PDBE
Revision 1.0Aug 28, 2019Provider: repository / Type: Initial release
Revision 1.1Jan 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

Downloads & links

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Assembly

Deposited unit
A: Ephrin type-A receptor 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,9672
Polymers34,4631
Non-polymers5041
Water4,846269
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 area14280 Å2
MethodPISA
Unit cell
Length a, b, c (Å)32.788, 107.240, 40.538
Angle α, β, γ (deg.)90.00, 108.61, 90.00
Int Tables number4
Space group name H-MP1211

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Components

#1: Protein Ephrin type-A receptor 2


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
#2: Chemical ChemComp-G0E / 4-methyl-3-[(1-methyl-6-pyrimidin-5-yl-pyrazolo[3,4-d]pyrimidin-4-yl)amino]-~{N}-[3-(trifluoromethyl)phenyl]benzamide


Mass: 504.467 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C25H19F3N8O / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 269 / 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: 37.24 %
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 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: 0.97627 Å
DetectorType: DECTRIS PILATUS 6M-F / Detector: PIXEL / Date: Dec 20, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97627 Å / Relative weight: 1
ReflectionResolution: 1.26→38.42 Å / Num. obs: 69838 / % possible obs: 98.2 % / Redundancy: 6.35 % / Biso Wilson estimate: 21.66 Å2 / CC1/2: 0.996 / Rrim(I) all: 0.203 / Net I/σ(I): 5.86
Reflection shellResolution: 1.26→1.34 Å / Redundancy: 5.98 % / Mean I/σ(I) obs: 0.25 / Num. unique obs: 10407 / CC1/2: 0.12 / % possible all: 91

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Processing

Software
NameVersionClassification
PHENIX(1.10.1_2155: ???)refinement
XDSXDSapp 2.0data reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6FNF

6fnf


Resolution: 1.268→38.418 Å / SU ML: 0.27 / Cross valid method: FREE R-VALUE / σ(F): 1.33 / Phase error: 30.36
RfactorNum. reflection% reflection
Rfree0.2211 2086 3 %
Rwork0.1969 --
obs0.1976 69424 99.31 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 1.268→38.418 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2168 0 37 270 2475
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0082339
X-RAY DIFFRACTIONf_angle_d0.9483166
X-RAY DIFFRACTIONf_dihedral_angle_d22.769903
X-RAY DIFFRACTIONf_chiral_restr0.082333
X-RAY DIFFRACTIONf_plane_restr0.005398
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.2683-1.29790.4261310.4494251X-RAY DIFFRACTION95
1.2979-1.33030.43221390.42514479X-RAY DIFFRACTION100
1.3303-1.36630.38321410.38894542X-RAY DIFFRACTION100
1.3663-1.40650.35161370.3624458X-RAY DIFFRACTION100
1.4065-1.45190.34251400.32334506X-RAY DIFFRACTION100
1.4519-1.50380.2961400.28024512X-RAY DIFFRACTION100
1.5038-1.5640.31221400.26324505X-RAY DIFFRACTION100
1.564-1.63520.25271390.23914508X-RAY DIFFRACTION100
1.6352-1.72140.22521390.2274511X-RAY DIFFRACTION100
1.7214-1.82920.25391400.21054491X-RAY DIFFRACTION100
1.8292-1.97050.19711400.19784515X-RAY DIFFRACTION100
1.9705-2.16870.21461400.17684509X-RAY DIFFRACTION100
2.1687-2.48250.2161390.16684484X-RAY DIFFRACTION99
2.4825-3.12750.18621400.16944515X-RAY DIFFRACTION99
3.1275-38.43550.17271410.14824552X-RAY DIFFRACTION99
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
10.94731.38941.43963.42541.45112.6839-0.0484-0.05880.0322-0.12140.332-0.48390.09860.2649-0.17140.3096-0.00770.01290.2722-0.09610.4144-63.2278-30.4043121.3483
21.72460.27050.17272.5391-1.28473.7359-0.0844-0.02810.1316-0.15080.21780.0980.10.0455-0.15960.27360.0084-0.03140.1531-0.02330.2999-68.8814-28.4732127.7983
30.3050.0701-0.04410.676-0.11910.2360.02290.0266-0.0782-0.0404-0.0139-0.02730.11190.0469-0.00650.217-0.0062-0.00510.182-0.00730.1848-63.2546-17.5378121.2191
40.87780.1896-0.31710.57460.30640.92550.0039-0.0569-0.06970.0291-0.0108-0.00740.09210.00510.0130.14760.00310.00430.15550.00760.1531-64.9944-8.6096130.9267
50.8609-0.07370.2980.7152-0.09550.9209-0.0403-0.06290.07160.0234-0.0027-0.0223-0.07590.0470.04210.14090.0022-0.0020.1460.00090.1368-61.02682.9856134.1829
64.5990.2904-0.26751.1568-0.47161.3126-0.0488-0.38210.0966-0.01130.0261-0.4446-0.00920.25960.06150.2714-0.00450.0110.2143-0.01530.3562-44.355914.0957129.3043
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'A' and (resid 605 through 632 )
2X-RAY DIFFRACTION2chain 'A' and (resid 633 through 669 )
3X-RAY DIFFRACTION3chain 'A' and (resid 670 through 712 )
4X-RAY DIFFRACTION4chain 'A' and (resid 713 through 795 )
5X-RAY DIFFRACTION5chain 'A' and (resid 796 through 881 )
6X-RAY DIFFRACTION6chain 'A' and (resid 882 through 896 )

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