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- PDB-8bio: Crystal structure of human Ephrin type-A receptor 2 (EPHA2) Kinas... -

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Basic information

Entry
Database: PDB / ID: 8bio
TitleCrystal structure of human Ephrin type-A receptor 2 (EPHA2) Kinase domain in complex with MRAL5
ComponentsEphrin type-A receptor 2
KeywordsTRANSFERASE / EPHA2 / ECK / Typ I Inhibitor
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-QRD / Ephrin type-A receptor 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.6 Å
AuthorsZhubi, R. / Rak, M. / Lucic, A. / Knapp, S. / Kraemer, A. / Structural Genomics Consortium (SGC)
Funding support Canada, 1items
OrganizationGrant numberCountry
The Structural Genomics Consortium (SGC) Canada
CitationJournal: Eur.J.Med.Chem. / Year: 2023
Title: Shifting the selectivity of pyrido[2,3-d]pyrimidin-7(8H)-one inhibitors towards the salt-inducible kinase (SIK) subfamily.
Authors: Rak, M. / Tesch, R. / Berger, L.M. / Shevchenko, E. / Raab, M. / Tjaden, A. / Zhubi, R. / Balourdas, D.I. / Joerger, A.C. / Poso, A. / Kramer, A. / Elson, L. / Lucic, A. / Kronenberger, T. / ...Authors: Rak, M. / Tesch, R. / Berger, L.M. / Shevchenko, E. / Raab, M. / Tjaden, A. / Zhubi, R. / Balourdas, D.I. / Joerger, A.C. / Poso, A. / Kramer, A. / Elson, L. / Lucic, A. / Kronenberger, T. / Hanke, T. / Strebhardt, K. / Sanhaji, M. / Knapp, S.
History
DepositionNov 2, 2022Deposition site: PDBE / Processing site: PDBE
Revision 1.0Nov 23, 2022Provider: repository / Type: Initial release
Revision 1.1Nov 22, 2023Group: Data collection / Database references
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Jan 31, 2024Group: Refinement description / Category: pdbx_initial_refinement_model

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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)35,69615
Polymers34,4631
Non-polymers1,23314
Water3,117173
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1840 Å2
ΔGint23 kcal/mol
Surface area13990 Å2
Unit cell
Length a, b, c (Å)32.840, 107.413, 40.651
Angle α, β, γ (deg.)90.00, 109.04, 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: Escherichia coli (E. coli)
References: UniProt: P29317, receptor protein-tyrosine kinase
#2: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 13 / Source method: obtained synthetically / Formula: C2H6O2
#3: Chemical ChemComp-QRD / 8-(4-azanylbutyl)-6-[2-chloranyl-5-(trifluoromethyl)phenyl]-2-(methylamino)pyrido[2,3-d]pyrimidin-7-one


Mass: 425.835 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C19H19ClF3N5O / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 173 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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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: 37.46 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 7.5
Details: 20% PEG3350, 10% ethylene glycol, 0.2M potassium thiocyanate

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06SA / Wavelength: 0.99999 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Oct 15, 2022
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.99999 Å / Relative weight: 1
ReflectionResolution: 1.6→28.43 Å / Num. obs: 227442 / % possible obs: 96.5 % / Redundancy: 6.7 % / CC1/2: 0.999 / Net I/σ(I): 15
Reflection shellResolution: 1.6→1.63 Å / Num. unique obs: 1329 / CC1/2: 0.72

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Processing

Software
NameVersionClassification
REFMAC5.8.0352refinement
Aimlessdata scaling
XDSdata reduction
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5NKA

5nka


Resolution: 1.6→38.46 Å / Cor.coef. Fo:Fc: 0.969 / Cor.coef. Fo:Fc free: 0.957 / SU B: 1.704 / SU ML: 0.058 / Cross valid method: THROUGHOUT / ESU R: 0.089 / ESU R Free: 0.09 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.1986 1763 5.2 %RANDOM
Rwork0.16312 ---
obs0.16498 32023 96.38 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 21.313 Å2
Baniso -1Baniso -2Baniso -3
1--0.1 Å20 Å2-0.19 Å2
2--1.09 Å20 Å2
3----0.69 Å2
Refinement stepCycle: 1 / Resolution: 1.6→38.46 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2135 0 81 173 2389
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0070.0122288
X-RAY DIFFRACTIONr_bond_other_d0.0010.0162145
X-RAY DIFFRACTIONr_angle_refined_deg1.3211.6533076
X-RAY DIFFRACTIONr_angle_other_deg0.4781.5724975
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.1475277
X-RAY DIFFRACTIONr_dihedral_angle_2_deg7.124515
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.08310386
X-RAY DIFFRACTIONr_dihedral_angle_4_deg
X-RAY DIFFRACTIONr_chiral_restr0.0720.2336
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.022634
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02446
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it1.6662.1911106
X-RAY DIFFRACTIONr_mcbond_other1.6662.1911107
X-RAY DIFFRACTIONr_mcangle_it2.4913.2631380
X-RAY DIFFRACTIONr_mcangle_other2.493.2631381
X-RAY DIFFRACTIONr_scbond_it2.6332.4141182
X-RAY DIFFRACTIONr_scbond_other2.6322.4161183
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other3.8313.5151696
X-RAY DIFFRACTIONr_long_range_B_refined5.59532.2352593
X-RAY DIFFRACTIONr_long_range_B_other5.59232.2332593
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.6→1.641 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.294 94 -
Rwork0.272 1870 -
obs--75.39 %

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