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- PDB-8boc: Crystal Structure of Ephrin A2 (EphA2) Receptor Protein Kinase wi... -

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Basic information

Entry
Database: PDB / ID: 8boc
TitleCrystal Structure of Ephrin A2 (EphA2) Receptor Protein Kinase with Compound 19
ComponentsEphrin type-A receptor 2
KeywordsTRANSFERASE / Inhibitor / Complex / Protein Tyrosine Kinase
Function / homology
Function and homology information


notochord cell development / notochord formation / blood vessel endothelial cell proliferation involved in sprouting angiogenesis / negative regulation of lymphangiogenesis / lens fiber cell morphogenesis / axial mesoderm formation / cAMP metabolic process / regulation of blood vessel endothelial cell migration / pericyte cell differentiation / ephrin receptor activity ...notochord cell development / notochord formation / blood vessel endothelial cell proliferation involved in sprouting angiogenesis / negative regulation of lymphangiogenesis / lens fiber cell morphogenesis / axial mesoderm formation / cAMP metabolic process / regulation of blood vessel endothelial cell migration / pericyte cell differentiation / ephrin receptor activity / leading edge membrane / negative regulation of chemokine production / response to growth factor / post-anal tail morphogenesis / activation of GTPase activity / bone remodeling / positive regulation of bicellular tight junction assembly / regulation of lamellipodium assembly / branching involved in mammary gland duct morphogenesis / EPH-Ephrin signaling / central nervous system neuron differentiation / RND1 GTPase cycle / RND2 GTPase cycle / tight junction / RND3 GTPase cycle / neural tube development / mammary gland epithelial cell proliferation / RHOV GTPase cycle / growth factor binding / EPHA-mediated growth cone collapse / regulation of cell adhesion mediated by integrin / RHOU GTPase cycle / lamellipodium membrane / RHOG GTPase cycle / EPH-ephrin mediated repulsion of cells / RAC2 GTPase cycle / RAC3 GTPase cycle / regulation of angiogenesis / ephrin receptor signaling pathway / regulation of ERK1 and ERK2 cascade / vasculogenesis / keratinocyte differentiation / RAC1 GTPase cycle / transmembrane receptor protein tyrosine kinase activity / cell surface receptor protein tyrosine kinase signaling pathway / osteoclast differentiation / molecular function activator activity / negative regulation of angiogenesis / skeletal system development / cell chemotaxis / protein localization to plasma membrane / positive regulation of protein localization to plasma membrane / cell motility / receptor protein-tyrosine kinase / ruffle membrane / intrinsic apoptotic signaling pathway in response to DNA damage / osteoblast differentiation / cell migration / lamellipodium / virus receptor activity / angiogenesis / 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 / Fibronectin type III domain / Growth factor receptor cysteine-rich domain superfamily / 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-QUF / Ephrin type-A receptor 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.9 Å
AuthorsLinhard, V. / Witt, K. / Gande, S. / Wollenhaupt, J. / Lennartz, F. / Weiss, M.S. / Schwalbe, H.
Funding support Germany, 1items
OrganizationGrant numberCountry
German Research Foundation (DFG) Germany
CitationJournal: Chemistry / Year: 2023
Title: Optimization of the Lead Compound NVP-BHG712 as a Colorectal Cancer Inhibitor.
Authors: Troster, A. / DiPrima, M. / Jores, N. / Kudlinzki, D. / Sreeramulu, S. / Gande, S.L. / Linhard, V. / Ludig, D. / Schug, A. / Saxena, K. / Reinecke, M. / Heinzlmeir, S. / Leisegang, M.S. / ...Authors: Troster, A. / DiPrima, M. / Jores, N. / Kudlinzki, D. / Sreeramulu, S. / Gande, S.L. / Linhard, V. / Ludig, D. / Schug, A. / Saxena, K. / Reinecke, M. / Heinzlmeir, S. / Leisegang, M.S. / Wollenhaupt, J. / Lennartz, F. / Weiss, M.S. / Kuster, B. / Tosato, G. / Schwalbe, H.
History
DepositionNov 15, 2022Deposition site: PDBE / Processing site: PDBE
Revision 1.0Nov 29, 2023Provider: repository / Type: Initial release
Revision 1.1Jun 12, 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.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year

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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)35,0342
Polymers34,4631
Non-polymers5711
Water66737
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration, also via NMR supported
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area14390 Å2
MethodPISA
Unit cell
Length a, b, c (Å)33.700, 71.720, 123.640
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number18
Space group name H-MP22121
Space group name HallP22ab(z,x,y)
Symmetry operation#1: x,y,z
#2: x,-y,-z
#3: -x,y+1/2,-z+1/2
#4: -x,-y+1/2,z+1/2
Components on special symmetry positions
IDModelComponents
11A-1137-

HOH

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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-QUF / ~{N}-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-3-[(1-methyl-6-pyridin-3-yl-pyrazolo[3,4-d]pyrimidin-4-yl)amino]benzamide


Mass: 571.476 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C27H19F6N7O / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 37 / 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: 2.17 Å3/Da / Density % sol: 43.26 %
Crystal growTemperature: 291 K / Method: vapor diffusion, sitting drop / pH: 8.5
Details: 37,5 % MPD_PEG 1000_PEG 3350, 175 mM Morpheus Carboxylic acids Mix, 100 mM Sodium citrate tribasic dihydrate, 100 mM Morpheus Buffer System 3 pH 8.5

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: BESSY / Beamline: 14.2 / Wavelength: 0.9184 Å
DetectorType: DECTRIS PILATUS 2M / Detector: PIXEL / Date: Dec 17, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9184 Å / Relative weight: 1
ReflectionResolution: 1.9→46.83 Å / Num. obs: 24427 / % possible obs: 99.8 % / Redundancy: 12.58 % / Biso Wilson estimate: 31.46 Å2 / CC1/2: 0.999 / Rrim(I) all: 0.173 / Net I/σ(I): 11.53
Reflection shellResolution: 1.9→2.02 Å / Mean I/σ(I) obs: 1.05 / Num. unique obs: 3854 / CC1/2: 0.633

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Processing

Software
NameVersionClassification
PHENIX1.20.1_4487refinement
XDSdata reduction
XDSdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5ia5

5ia5


Resolution: 1.9→35.73 Å / SU ML: 0.3108 / Cross valid method: FREE R-VALUE / σ(F): 1.36 / Phase error: 32.0078
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2856 1217 4.99 %
Rwork0.246 23153 -
obs0.2479 24370 99.69 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 46.98 Å2
Refinement stepCycle: LAST / Resolution: 1.9→35.73 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2161 0 41 37 2239
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00422314
X-RAY DIFFRACTIONf_angle_d0.74963134
X-RAY DIFFRACTIONf_chiral_restr0.0439337
X-RAY DIFFRACTIONf_plane_restr0.0114439
X-RAY DIFFRACTIONf_dihedral_angle_d5.7215344
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.9-1.980.39841340.38882528X-RAY DIFFRACTION99.66
1.98-2.070.37231310.34272503X-RAY DIFFRACTION99.28
2.07-2.180.33531330.30882508X-RAY DIFFRACTION99.59
2.18-2.310.33681330.28782557X-RAY DIFFRACTION99.78
2.31-2.490.35861340.2852538X-RAY DIFFRACTION99.81
2.49-2.740.32051350.27052565X-RAY DIFFRACTION99.78
2.74-3.140.28661350.26322588X-RAY DIFFRACTION99.89
3.14-3.950.28141380.21352616X-RAY DIFFRACTION99.96
3.95-35.730.22371440.20172750X-RAY DIFFRACTION99.48
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)
11.993706834090.4666633720940.3520419720521.59407054791-1.698555923032.925339131090.09720792288720.0882767115727-0.2716442620340.3471134342840.337117671470.05003120902290.216975079764-0.534299840593-0.3700854922940.4622293789540.183077646499-0.06078536062710.430731211984-0.01947609377030.36346399426625.361492691312.244711723823.1724019133
20.4580387464360.352485185484-0.08349853044843.71823717582-0.06831332810190.284385957988-0.3521057099990.05123867265740.0452020764777-0.0630270956920.705330270716-0.284913289719-0.07637843422790.0130059130074-0.2364280029350.2079753934430.02650924355430.007701379972990.405949482883-0.07740971520370.27291650804829.680719535320.4079185473.87341110602
Refinement TLS group

Refine-ID: X-RAY DIFFRACTION / Auth asym-ID: A / Label asym-ID: A

IDRefine TLS-IDSelection detailsAuth seq-IDLabel seq-ID
11chain 'A' and (resid 605 through 752 )605 - 7521 - 135
22chain 'A' and (resid 753 through 888 )753 - 888136 - 271

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