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

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Basic information

Entry
Database: PDB / ID: 8qqy
TitleCrystal structure of human Ephrin type-A receptor 2 (EPHA2) Kinase domain in complex with JG165
ComponentsEphrin type-A receptor 2
KeywordsTRANSFERASE / EPHA2 / Ephrin type-A receptor 2 / Inhibitor / Macrocycle / Structural Genomics / Structural Genomics Consortium / SGC
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 / response to growth factor / bone remodeling / positive regulation of bicellular tight junction assembly / activation of GTPase activity / regulation of lamellipodium assembly / branching involved in mammary gland duct morphogenesis / EPH-Ephrin signaling / tight junction / RND1 GTPase cycle / neural tube development / 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 / regulation of angiogenesis / regulation of ERK1 and ERK2 cascade / vasculogenesis / keratinocyte differentiation / transmembrane receptor protein tyrosine kinase activity / RAC1 GTPase cycle / osteoclast differentiation / cell surface receptor protein tyrosine kinase signaling pathway / negative regulation of angiogenesis / molecular function activator activity / protein localization to plasma membrane / skeletal system development / cell chemotaxis / positive regulation of protein localization to plasma membrane / 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 / transmembrane-ephrin receptor activity / GPI-linked ephrin receptor activity / epidermal growth factor receptor activity / fibroblast growth factor receptor activity / insulin-like growth factor receptor activity / receptor protein-tyrosine kinase / ruffle membrane / intrinsic apoptotic signaling pathway in response to DNA damage / neuron differentiation / osteoblast differentiation / cell migration / lamellipodium / virus receptor activity / angiogenesis / receptor complex / defense response to Gram-positive bacterium / cell adhesion / 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 / 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
Similarity search - Domain/homology
Chem-WT3 / Ephrin type-A receptor 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.8 Å
AuthorsZhubi, R. / Gerninghaus, J. / Knapp, S. / Kraemer, A. / Structural Genomics Consortium (SGC)
Funding support Canada, 1items
OrganizationGrant numberCountry
The Structural Genomics Consortium (SGC) Canada
Citation
Journal: J.Med.Chem. / Year: 2024
Title: Back-Pocket Optimization of 2-Aminopyrimidine-Based Macrocycles Leads to Potent EPHA2/GAK Kinase Inhibitors.
Authors: Gerninghaus, J. / Zhubi, R. / Kramer, A. / Karim, M. / Tran, D.H.N. / Joerger, A.C. / Schreiber, C. / Berger, L.M. / Berger, B.T. / Ehret, T.A.L. / Elson, L. / Lenz, C. / Saxena, K. / ...Authors: Gerninghaus, J. / Zhubi, R. / Kramer, A. / Karim, M. / Tran, D.H.N. / Joerger, A.C. / Schreiber, C. / Berger, L.M. / Berger, B.T. / Ehret, T.A.L. / Elson, L. / Lenz, C. / Saxena, K. / Muller, S. / Einav, S. / Knapp, S. / Hanke, T.
#1: Journal: Curr Res Chem Biol / Year: 2022
Title: IPP/CNRS-A017: A chemical probe for human dihydroorotate dehydrogenase (hDHODH)
Authors: Kramer, A. / Tjaden, A. / Ndreshkjana, B. / Tredup, C. / Farin, H.F. / Knapp, S. / Janin, Y.L. / Muller, S.
History
DepositionOct 6, 2023Deposition site: PDBE / Processing site: PDBE
Revision 1.0Nov 22, 2023Provider: repository / Type: Initial release
Revision 1.1Jul 31, 2024Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.pdbx_database_id_DOI / _citation.title / _citation.year
Revision 1.2Nov 27, 2024Group: Database references / Structure summary / Category: citation / citation_author / pdbx_entry_details / Item: _pdbx_entry_details.has_protein_modification

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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)35,69915
Polymers34,4631
Non-polymers1,23614
Water2,702150
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2240 Å2
ΔGint29 kcal/mol
Surface area13520 Å2
MethodPISA
Unit cell
Length a, b, c (Å)32.818, 107.676, 40.636
Angle α, β, γ (deg.)90.00, 109.18, 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-WT3 / 6-(4-fluoranyl-3-methoxy-phenyl)-13$l^{6}-thia-2,4,8,12,19-pentazatricyclo[12.3.1.1^{3,7}]nonadeca-1(18),3,5,7(19),14,16-hexaene 13,13-dioxide


Mass: 429.468 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C20H20FN5O3S / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 13 / Source method: obtained synthetically / Formula: C2H6O2
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 150 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Has protein modificationN

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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: 293 K / Method: vapor diffusion / Details: 20% PEG3350 10% ethylene glycol 0.2M sodium iodide

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06DA / Wavelength: 0.918396 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Mar 20, 2022
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.918396 Å / Relative weight: 1
ReflectionResolution: 1.8→38.41 Å / Num. obs: 24679 / % possible obs: 100 % / Redundancy: 6.9 % / CC1/2: 0.998 / Net I/σ(I): 12.6
Reflection shellResolution: 1.8→1.84 Å / Num. unique obs: 1466 / CC1/2: 0.75

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Processing

Software
NameVersionClassification
REFMAC5.8.0419refinement
Aimlessdata scaling
XDSdata reduction
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.8→38.41 Å / Cor.coef. Fo:Fc: 0.947 / Cor.coef. Fo:Fc free: 0.92 / SU B: 3.017 / SU ML: 0.094 / Cross valid method: THROUGHOUT / ESU R: 0.143 / ESU R Free: 0.13 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.22328 1155 4.7 %RANDOM
Rwork0.189 ---
obs0.19065 23494 99.97 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 19.295 Å2
Baniso -1Baniso -2Baniso -3
1--0.71 Å2-0 Å2-0.35 Å2
2--1.44 Å20 Å2
3----0.39 Å2
Refinement stepCycle: 1 / Resolution: 1.8→38.41 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2145 0 82 150 2377
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0080.0122278
X-RAY DIFFRACTIONr_bond_other_d0.0020.0162191
X-RAY DIFFRACTIONr_angle_refined_deg1.5161.6593060
X-RAY DIFFRACTIONr_angle_other_deg0.5331.5885023
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.385271
X-RAY DIFFRACTIONr_dihedral_angle_2_deg13.263517
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.82710384
X-RAY DIFFRACTIONr_dihedral_angle_4_deg
X-RAY DIFFRACTIONr_chiral_restr0.080.2334
X-RAY DIFFRACTIONr_gen_planes_refined0.0080.022727
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02519
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_it1.8121.9421094
X-RAY DIFFRACTIONr_mcbond_other1.8111.9421095
X-RAY DIFFRACTIONr_mcangle_it2.7213.4611361
X-RAY DIFFRACTIONr_mcangle_other2.723.4611362
X-RAY DIFFRACTIONr_scbond_it2.3192.1431184
X-RAY DIFFRACTIONr_scbond_other2.3182.1441185
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other3.4653.8411700
X-RAY DIFFRACTIONr_long_range_B_refined4.32125.824669
X-RAY DIFFRACTIONr_long_range_B_other4.3225.824670
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.8→1.847 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.266 102 -
Rwork0.24 1711 -
obs--100 %

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