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

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Basic information

Entry
Database: PDB / ID: 8boh
TitleCrystal Structure of Ephrin A2 (EphA2) Receptor Protein Kinase with Compound 8
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 / ephrin receptor activity / leading edge membrane / negative regulation of chemokine production / post-anal tail morphogenesis / bone remodeling / response to growth factor / activation of GTPase activity / tight junction / regulation of lamellipodium assembly / 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 / 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 / negative regulation of angiogenesis / regulation of ERK1 and ERK2 cascade / osteoclast differentiation / cell chemotaxis / molecular function activator activity / skeletal system development / protein localization to plasma membrane / cell motility / positive regulation of protein localization to plasma membrane / receptor protein-tyrosine kinase / neuron differentiation / ruffle membrane / osteoblast differentiation / intrinsic apoptotic signaling pathway in response to DNA damage / cell migration / lamellipodium / virus receptor 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 / 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-R0T / Ephrin type-A receptor 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.42 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

Downloads & links

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)35,0462
Polymers34,4631
Non-polymers5841
Water3,315184
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 area13910 Å2
Unit cell
Length a, b, c (Å)32.700, 106.580, 40.390
Angle α, β, γ (deg.)90.000, 108.520, 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-R0T / 4-methyl-~{N}-[3-(4-methylimidazol-1-yl)-5-(trifluoromethyl)phenyl]-3-[(1-methyl-6-pyridin-3-yl-pyrazolo[3,4-d]pyrimidin-4-yl)amino]benzamide


Mass: 583.566 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C30H24F3N9O / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 184 / 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: 1.94 Å3/Da / Density % sol: 36.48 %
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 Tris-HCl 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 Tris-HCl 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: 14.1 / Wavelength: 0.9184 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Oct 23, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9184 Å / Relative weight: 1
ReflectionResolution: 1.42→38.3 Å / Num. obs: 49017 / % possible obs: 98.7 % / Redundancy: 6.8 % / Biso Wilson estimate: 23.17 Å2 / CC1/2: 1 / Rrim(I) all: 0.011 / Net I/σ(I): 11.52
Reflection shellResolution: 1.42→1.5 Å / Redundancy: 6.57 % / Mean I/σ(I) obs: 1.08 / Num. unique obs: 7704 / CC1/2: 0.48 / Rrim(I) all: 0.174 / % possible all: 96.4

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Processing

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

6q7d


Resolution: 1.42→38.3 Å / SU ML: 0.1609 / Cross valid method: FREE R-VALUE / σ(F): 1.36 / Phase error: 18.6317
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.1742 2099 4.28 %
Rwork0.158 46913 -
obs0.1587 49012 98.82 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 22.79 Å2
Refinement stepCycle: LAST / Resolution: 1.42→38.3 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2151 0 43 184 2378
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.01172406
X-RAY DIFFRACTIONf_angle_d1.1373275
X-RAY DIFFRACTIONf_chiral_restr0.0877346
X-RAY DIFFRACTIONf_plane_restr0.016471
X-RAY DIFFRACTIONf_dihedral_angle_d12.8312949
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.42-1.450.32531290.32852879X-RAY DIFFRACTION91.51
1.45-1.490.28431430.27523201X-RAY DIFFRACTION99.94
1.49-1.530.27211380.24983092X-RAY DIFFRACTION99.94
1.53-1.570.26531410.23583142X-RAY DIFFRACTION99.64
1.57-1.620.22911410.21793157X-RAY DIFFRACTION99.31
1.62-1.680.23161390.20093093X-RAY DIFFRACTION98.72
1.68-1.750.21331390.19183115X-RAY DIFFRACTION97.86
1.75-1.830.19981420.16493162X-RAY DIFFRACTION99.85
1.83-1.920.16561420.14693172X-RAY DIFFRACTION99.67
1.92-2.040.17371400.14373149X-RAY DIFFRACTION99.82
2.04-2.20.15631380.13393070X-RAY DIFFRACTION97.92
2.2-2.420.15411410.13923163X-RAY DIFFRACTION99.94
2.42-2.770.1621420.13883163X-RAY DIFFRACTION99.61
2.77-3.490.15111410.14513151X-RAY DIFFRACTION99.1
3.49-38.30.14571430.13793204X-RAY DIFFRACTION99.41
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)
15.336058761681.472410498961.088847885592.45892858371-0.9249997679332.559355973250.0349180510302-0.1327803397430.445312650376-0.3214964481150.292626264606-0.106491420732-0.0433678950765-0.025633997933-0.3290884695630.281949104092-0.0163945125507-0.03274695862220.199640008163-0.06620733867130.357235303776-87.246145686-31.036321925579.8383342848
25.865333534090.5172027516151.050471801394.2616069489-2.901981299914.479448653880.103199620251-0.126861569146-0.2958542492520.09337255126310.111849921956-0.5118119351270.2815498505130.506665887366-0.2209333892520.2836444028380.002139750255350.02351366974930.169428723385-0.07613374483180.358588117871-80.1930390327-28.039060167583.7325984336
30.9233212272780.2498866172330.08172998943382.83281702584-2.742461640175.10659316418-0.0555634839288-0.1354373310560.08522865690350.09592038992150.2062835546330.222635224476-0.0183539259791-0.0240510432048-0.1172583890190.1958879841830.0211509653576-0.01940987328440.108024647723-0.005404042320950.24645876599-88.7860428657-27.807397865291.5277702785
40.162853331928-0.806531935108-0.08435106087918.50449248605-0.6558621425950.5598913959440.08036013018360.0351245270598-0.164397054952-0.1595924989-0.05896895266590.385437188130.197702333164-0.0490191113856-0.01558796268580.183532354789-0.0112993039057-0.02403667850360.160643051356-0.005594416255830.17407962938-91.4298757334-22.633545626583.1392824977
52.180927084392.65411017691-0.803976891394.47668323507-1.200973149450.744217283563-0.116416726950.0488561957783-0.138780374442-0.3066696436560.07180447299-0.07519605737070.1604047527290.08338695241750.03403195904030.1686772330150.004274404664990.004390334922110.181556947296-0.01086170110820.152613248715-76.1722554016-12.114847491982.0793064373
61.659944413340.0126063740234-0.4889621418731.197745094750.0783588600861.02903533829-0.01669090567540.05667738306-0.0437068333899-0.04577510512010.01837309548970.02008563525660.0112623481746-0.0105499379976-0.0004519182507310.114191041147-0.007259401288860.005427109392840.137850974782-0.005604689152930.10927505342-85.5761264573-7.0522068041986.7714922805
70.2436542240450.2669832405820.3441536279520.5959500378751.015730262082.093441108480.00726753293994-0.0966390599415-0.06884680792470.08666228428050.0111022762257-0.05315224073710.1817233492070.0705341183947-0.00578607532150.1757883686980.000980359234242-0.0008206784393820.1998597559320.03312262489480.137325920661-83.3097894315-9.29079909906103.33944789
81.24584214319-0.1166649463990.107436714231.24088168871-0.1351770532940.911571665215-0.0443382691402-0.07644940437820.03125522737230.05727175173240.0215169151416-0.11637257731-0.02083111349090.09011064512440.01733925802130.1168103983920.00655866888099-0.0002056211684720.158315359064-0.003825535144450.127139509392-75.35261838490.6503790179898.2979006844
91.513907336540.1847273662120.5310103509351.70757041323-1.021783486063.26310145529-0.0358223586372-0.0607334842980.0931135933160.03094312579740.01051272614270.0218322092094-0.153581052458-0.1353193747730.006178914209860.1354246419210.02017670660620.003746417334290.12227253745-0.01358524036910.14502588412-87.29896809596.5897446201793.4605621474
102.613591655590.7820778205060.5306151759771.861239677160.1770150871471.95470456406-0.0627511671499-0.428771150316-0.1207956003460.09557203832580.048023827879-0.5604944310840.03377655986410.256544071526-0.0007356429972570.198363480641-0.00488978938762-0.02331813671790.2250013242340.00790538008490.354469148261-64.093164731114.417832273890.9061183571
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 604 through 618 )604 - 6181 - 15
22chain 'A' and (resid 619 through 640 )619 - 64016 - 31
33chain 'A' and (resid 641 through 669 )641 - 66932 - 60
44chain 'A' and (resid 670 through 687 )670 - 68761 - 78
55chain 'A' and (resid 688 through 712 )688 - 71279 - 103
66chain 'A' and (resid 713 through 755 )713 - 755104 - 146
77chain 'A' and (resid 756 through 795 )756 - 795147 - 168
88chain 'A' and (resid 796 through 843 )796 - 843169 - 216
99chain 'A' and (resid 844 through 881 )844 - 881217 - 254
1010chain 'A' and (resid 882 through 896 )882 - 896255 - 269

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