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

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Basic information

Entry
Database: PDB / ID: 8bog
TitleCrystal Structure of Ephrin A2 (EphA2) Receptor Protein Kinase with Compound 7
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 / 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-QUU / Ephrin type-A receptor 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.47 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 1.0Mar 8, 2023Provider: repository / Type: Initial release
Revision 1.1Mar 15, 2023Group: Database references / Category: citation / Item: _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.2Mar 22, 2023Group: Database references / Category: citation / Item: _citation.page_first / _citation.page_last
Revision 1.3Apr 5, 2023Group: Database references / Category: citation / citation_author / Item: _citation.title / _citation_author.identifier_ORCID
Revision 1.4May 3, 2023Group: Database references / Category: citation / Item: _citation.journal_volume
Revision 1.5Feb 7, 2024Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / 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)34,9662
Polymers34,4631
Non-polymers5031
Water2,864159
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration, Also verified by NMR
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area14020 Å2
Unit cell
Length a, b, c (Å)32.570, 106.220, 40.270
Angle α, β, γ (deg.)90.000, 108.510, 90.000
Int Tables number4
Space group name H-MP1211
Space group name HallP2yb
Symmetry operation#1: x,y,z
#2: -x,y+1/2,-z

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


Mass: 503.479 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C26H20F3N7O / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 159 / 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: 1.92 Å3/Da / Density % sol: 35.83 %
Crystal growTemperature: 291 K / Method: vapor diffusion, sitting drop / pH: 6.5
Details: 37,5 % Precipitant Mix 4 (25% (v/v) Hexylene glycol, 25% (w/v) Poly(ethylene glycol) 1000, 25% (w/v) Poly(ethylene glycol) 3350), 0.1M Bis-Tris pH 6.5, 0.1 M Amino acids mix (0.2 M DL- ...Details: 37,5 % Precipitant Mix 4 (25% (v/v) Hexylene glycol, 25% (w/v) Poly(ethylene glycol) 1000, 25% (w/v) Poly(ethylene glycol) 3350), 0.1M Bis-Tris pH 6.5, 0.1 M Amino acids mix (0.2 M DL-Alanine, 0.2M DL-Glutamic acid monohydrate, 0.2M DL-Lysine monohydrochloride, 0.2M DL-Serine, 0.2M Glycine)

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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 1, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9184 Å / Relative weight: 1
ReflectionResolution: 1.47→38.19 Å / Num. obs: 44065 / % possible obs: 99.6 % / Redundancy: 6.74 % / Biso Wilson estimate: 24.11 Å2 / CC1/2: 1 / Rrim(I) all: 0.014 / Net I/σ(I): 9.79
Reflection shellResolution: 1.47→1.56 Å / Redundancy: 6.59 % / Mean I/σ(I) obs: 0.87 / Num. unique obs: 7045 / CC1/2: 0.37 / Rrim(I) all: 0.199 / % possible all: 98.3

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Processing

Software
NameVersionClassification
PHENIX1.20.1_4487refinement
XDSdata reduction
XDSdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6q7d

6q7d


Resolution: 1.47→38.19 Å / SU ML: 0.1844 / Cross valid method: FREE R-VALUE / σ(F): 1.36 / Phase error: 20.8993
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.18 2100 4.77 %
Rwork0.1662 41952 -
obs0.1669 44052 99.72 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 24.99 Å2
Refinement stepCycle: LAST / Resolution: 1.47→38.19 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2172 0 37 159 2368
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00432409
X-RAY DIFFRACTIONf_angle_d0.783270
X-RAY DIFFRACTIONf_chiral_restr0.0641348
X-RAY DIFFRACTIONf_plane_restr0.0105459
X-RAY DIFFRACTIONf_dihedral_angle_d12.5851941
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.47-1.50.34131360.32122711X-RAY DIFFRACTION96.41
1.5-1.540.34031400.30592799X-RAY DIFFRACTION99.9
1.54-1.580.3041390.28692773X-RAY DIFFRACTION99.93
1.58-1.630.27041410.27042814X-RAY DIFFRACTION100
1.63-1.680.3091400.24962794X-RAY DIFFRACTION99.97
1.68-1.740.27071390.22242791X-RAY DIFFRACTION99.97
1.74-1.810.23691410.1992810X-RAY DIFFRACTION99.97
1.81-1.890.18571390.17122774X-RAY DIFFRACTION100
1.89-1.990.18861400.16742789X-RAY DIFFRACTION99.9
1.99-2.120.18411410.1482826X-RAY DIFFRACTION100
2.12-2.280.1641400.13842794X-RAY DIFFRACTION100
2.28-2.510.16821410.14092823X-RAY DIFFRACTION100
2.51-2.870.17151400.14192798X-RAY DIFFRACTION100
2.87-3.620.13711420.1422827X-RAY DIFFRACTION100
3.62-38.190.13811410.14612829X-RAY DIFFRACTION99.76
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)
11.816270799330.7746401405351.369263754333.57927868015-0.5009363346492.40148177242-0.0970188068055-0.3443081124410.465349111573-0.319833323430.2928717021460.072474303542-0.138464899713-0.0848004658777-0.2214172043020.247136462671-0.02726099666070.0005976571931490.241832651268-0.074231341150.320896602988-89.2444456616-29.748007745781.6037667572
24.545865014250.4021867087121.008867929614.13140081683-1.885405193342.003480774170.05925708709420.0771541607778-0.245349057627-0.03641952157890.205392203036-0.503113616569-0.1711591000880.359556216589-0.276697676010.265038597545-0.03763208037220.03548240385280.205541330552-0.0706211079160.3551788666-80.2907012379-28.302789246183.1804752286
31.671817362170.6618654614310.002730588070933.32666516322-1.96941005835.18351631184-0.0724556445995-0.1099121715870.03234494798230.005534380717610.1378635322150.0495150466410.05673262754290.0548744609072-0.04617838863190.179377503786-0.00208767075431-0.002137249955630.15915466016-0.01638017950570.219097771351-88.4428163001-27.642166196991.4905324845
40.113140707755-0.674546538624-0.07454819590969.04234512012-0.8139767921050.3500755084460.03122559902320.0224348513139-0.115971703834-0.1134276204250.005534189813860.3745256539430.101431353252-0.0675997539858-0.03398245652930.185207359474-0.0122330108869-0.01691053716270.189359122969-0.007098563776720.211105791769-90.805927372-22.77984680783.1103024863
51.538042015692.18484196982-0.7724648271023.15759405122-1.054313655910.631976240484-0.1144983654570.0175845257318-0.130703043717-0.2667052006490.0515492110856-0.07189256719760.1516482724830.02898273729930.05846955167330.168901859454-0.0008530582550510.006165675144620.184031145861-0.008759986075330.172418152626-75.2624223779-12.104263776981.5895633478
61.91168271653-0.0124257223883-0.9457092059661.266180097270.1717687748271.4033464908-0.01169846372120.0341441348238-0.0509026404766-0.01405076450530.002722230485260.02921155041830.0402672627195-0.007522068388140.01105419000350.1294130406110.00231280579853-0.006376580583630.141935752821-0.008946496072660.142909247941-84.67214266-6.8381109050685.7748787676
70.5455683500140.2633602959660.5149396185210.6015226359521.068092238362.1332144053-0.0548048281065-0.0707040934896-0.03406554722380.04392649739790.054013791384-0.0237567651790.2237552773740.1248648144690.04607849033470.192729575920.01085024564050.004891461480050.2035191503650.02957569450940.158470304021-82.632207549-8.95964596063102.600471491
81.095424022990.0123924384610.3212351625030.867632138166-0.1407778353950.933756195429-0.0603475862015-0.102846678668-0.01063326931910.06479366393260.0177077216376-0.1011787616090.03612158574730.07683159158830.0294853511360.1441994956010.0132179889511-0.0009962634150540.1691358779840.002914208501140.159687956756-74.9699242014-1.6817228212398.766229262
91.741077087740.2100576760681.009282174012.10753896835-0.6802220530591.4391302579-0.0864596991687-0.1244282828670.07997123881260.1398529200060.0280713274237-0.0231642173419-0.0276861111203-0.06228526119990.03667348294120.1565095719570.0208230530617-0.005579215197540.136721529012-0.02330855543080.133621372016-81.10111198576.5526842280797.656706646
101.945219316460.973166187931-1.223544030832.69680646116-2.336910438524.33600852594-0.01882403685510.1860741278090.0115313521891-0.0616555223099-0.004465497042420.0416199840314-0.112785971031-0.141709469766-0.01470159314380.174142263210.0202346302228-0.008209305423770.160312507025-0.004282519774760.176511288642-88.05337294427.7265699829983.275751331
118.574678366460.349851742954-0.5640037143953.07787322675-0.7974947301732.171071342590.00403937123235-0.737536721787-0.3979774424550.100025396343-0.0313005156251-0.4016652063890.2500722607280.256343192830.03941196616690.2519168760420.03726824878490.01713669106070.205045774330.01103496681210.294193036343-64.109952769114.052648035490.5741117334
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 600 through 618 )600 - 6181 - 19
22chain 'A' and (resid 619 through 640 )619 - 64020 - 36
33chain 'A' and (resid 641 through 669 )641 - 66937 - 65
44chain 'A' and (resid 670 through 687 )670 - 68766 - 83
55chain 'A' and (resid 688 through 712 )688 - 71284 - 108
66chain 'A' and (resid 713 through 755 )713 - 755109 - 151
77chain 'A' and (resid 756 through 795 )756 - 795152 - 172
88chain 'A' and (resid 796 through 831 )796 - 831173 - 208
99chain 'A' and (resid 832 through 863 )832 - 863209 - 240
1010chain 'A' and (resid 864 through 881 )864 - 881241 - 258
1111chain 'A' and (resid 882 through 895 )882 - 895259 - 272

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