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

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Basic information

Entry
Database: PDB / ID: 8bod
TitleCrystal Structure of Ephrin A2 (EphA2) Receptor Protein Kinase with Compound 20
ComponentsEphrin type-A receptor 2
KeywordsTRANSFERASE / Inhibitor / Complex / Protein Tyropsine 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 / regulation of ERK1 and ERK2 cascade / negative regulation of angiogenesis / osteoclast differentiation / cell chemotaxis / skeletal system development / molecular function activator activity / protein localization to plasma membrane / cell motility / positive regulation of protein localization to plasma membrane / receptor protein-tyrosine kinase / neuron differentiation / ruffle membrane / intrinsic apoptotic signaling pathway in response to DNA damage / osteoblast differentiation / cell migration / lamellipodium / virus receptor activity / receptor complex / cell adhesion / defense response to Gram-positive bacterium / positive regulation of cell migration / inflammatory response / cadherin binding / 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-QTX / Ephrin type-A receptor 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.5 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)34,9672
Polymers34,4631
Non-polymers5041
Water5,386299
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 area13960 Å2
Unit cell
Length a, b, c (Å)32.720, 107.250, 40.550
Angle α, β, γ (deg.)90.000, 108.730, 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-QTX / ~{N}-[3,5-bis(chloranyl)phenyl]-4-methyl-3-[(1-methyl-6-pyridin-3-yl-pyrazolo[3,4-d]pyrimidin-4-yl)amino]benzamide


Mass: 504.371 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C25H19Cl2N7O / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 299 / 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: 1.96 Å3/Da / Density % sol: 37.09 %
Crystal growTemperature: 291 K / Method: vapor diffusion, sitting drop / pH: 6
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 Mes pH 6.0, 0.1 M Amino acids mix (0.2 M DL-Alanine, 0. ...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 Mes pH 6.0, 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: Oct 5, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9184 Å / Relative weight: 1
ReflectionResolution: 1.5→38.41 Å / Num. obs: 42245 / % possible obs: 99.6 % / Redundancy: 6.82 % / Biso Wilson estimate: 22.31 Å2 / CC1/2: 0.99 / Rrim(I) all: 0.014 / Net I/σ(I): 8.48
Reflection shellResolution: 1.5→1.59 Å / Mean I/σ(I) obs: 1.36 / Num. unique obs: 6717 / CC1/2: 0.58 / Rrim(I) all: 0.13

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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: 1.5→38.4 Å / SU ML: 0.1609 / Cross valid method: FREE R-VALUE / σ(F): 1.36 / Phase error: 19.5087
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.1854 2099 4.97 %
Rwork0.1604 40128 -
obs0.1616 42227 99.69 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 22.89 Å2
Refinement stepCycle: LAST / Resolution: 1.5→38.4 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2139 0 35 299 2473
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00522319
X-RAY DIFFRACTIONf_angle_d0.91493149
X-RAY DIFFRACTIONf_chiral_restr0.0662337
X-RAY DIFFRACTIONf_plane_restr0.0157445
X-RAY DIFFRACTIONf_dihedral_angle_d12.2651902
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.5-1.530.30431340.27662575X-RAY DIFFRACTION96.61
1.53-1.570.28261410.25212683X-RAY DIFFRACTION99.86
1.57-1.610.28781390.23972670X-RAY DIFFRACTION99.86
1.61-1.660.27131400.22692666X-RAY DIFFRACTION99.93
1.66-1.720.23481410.21042689X-RAY DIFFRACTION100
1.72-1.780.23731380.19962651X-RAY DIFFRACTION99.96
1.78-1.850.18311420.1812701X-RAY DIFFRACTION99.96
1.85-1.930.19281400.16662689X-RAY DIFFRACTION100
1.93-2.030.15981410.15912686X-RAY DIFFRACTION99.96
2.03-2.160.19071400.14652680X-RAY DIFFRACTION99.96
2.16-2.330.17171390.13772664X-RAY DIFFRACTION99.96
2.33-2.560.16421410.13952689X-RAY DIFFRACTION99.89
2.56-2.930.18221400.14712680X-RAY DIFFRACTION99.93
2.93-3.690.1571420.13962702X-RAY DIFFRACTION99.96
3.7-38.40.16351410.14422703X-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)
14.319641224561.416251821211.550751498932.48284979768-0.7955606992493.103157896750.0823794869521-0.1436012022280.264388464427-0.344635577490.270517105535-0.2491732599380.1022935081450.173488718218-0.3233239525770.247121930826-0.01943999212060.00473982172110.198931573172-0.1092486839460.325464431527-86.3731461757-31.370859774579.5404139889
24.814359130160.5814903027770.09766660387083.87554535866-1.403154388127.008082775860.0363806718865-0.117523377359-0.218876138483-0.007471411780130.233650145612-0.4974816840610.2033397570120.294604603322-0.2966672953490.245967201806-0.002025200127350.03692565279040.225551498404-0.1195447118560.398681682315-81.5228613356-27.850774780883.3762728258
30.6443766405080.1391844679850.2259036489862.8465110648-2.442790891524.42819302372-0.00223401456832-0.1215882228350.03613252756120.1870346924890.2590551583670.226186217298-0.09197962492480.0149253999813-0.2141191309950.2038986155410.01876083856930.01256370766110.133801738030.001766414321240.26635461568-89.4677612699-27.749770763691.73447481
40.7033753693480.354222769653-0.1342748258971.34714857672-0.2523874264230.541691723991-0.01167311977140.0431545013721-0.113788003605-0.08471444674590.0019080229169-0.00579664417430.1390082539050.0341623762990.008653811771660.1375242819250.000983234100340.005856644484270.140052516623-0.009055561154110.13238301798-82.7322527863-16.11859486482.849883909
51.897477519590.118623966241-0.5143895780181.151792324010.08739352344641.33060933765-0.007283664686730.0348649427861-0.0582205476781-0.0007318641779070.01097549741190.03080303572710.0152135935179-0.0230249375792-0.001393237817950.0763083236914-0.008510456730050.005866569799150.116431836002-0.0004231743314810.0973124726605-85.9730461864-6.787260446387.2120684144
61.126472714440.203155800063-0.05996621518810.616162441659-0.03733697845291.41321252814-0.0260248456713-0.105580052883-0.06119707784890.0312582510353-0.000386010741588-0.09002922580550.1036631018930.05718030396620.02068232540260.08159877890160.00611990373580.005391852973230.1228698058810.0118816885360.108529153515-80.2277728742-4.6014813904199.2105334195
71.84968499381-0.21539699360.7927479534711.49161240525-0.6165243613572.0543957394-0.0435949648735-0.1569552892520.0569718072150.120004835252-0.0101865927056-0.0658640459946-0.08028913100760.02724515053490.05204955458190.1120061317630.008066620712460.001619015664660.126220085763-0.0143222811210.118122689291-80.27125894865.21636309948100.768054021
82.870166670332.03156249068-2.138617752354.39008156845-3.454969755125.32331548889-0.001601573459830.1371265176160.158372022822-0.1128378492920.08041420350160.178513036904-0.112437434396-0.20460235764-0.0853103934440.1124107394810.00997287258914-0.008283766947660.1112613174970.01003854385990.123293220609-89.45458594627.8257751561284.1145287059
98.649579374541.231573220380.04768936928352.14600199353-0.1007869523521.637626027510.0321404810448-0.52265266403-0.08753954989720.112937334869-0.0588646613201-0.4901163764590.02053324137750.2617585723570.02882457180870.201647695501-0.00271119710205-0.008830233498220.198112477930.008059353341150.329162191365-64.48742317414.711338375491.3179004712
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 618 )605 - 6181 - 14
22chain 'A' and (resid 619 through 640 )619 - 64015 - 31
33chain 'A' and (resid 641 through 669 )641 - 66932 - 60
44chain 'A' and (resid 670 through 712 )670 - 71261 - 103
55chain 'A' and (resid 713 through 755 )713 - 755104 - 146
66chain 'A' and (resid 756 through 822 )756 - 822147 - 194
77chain 'A' and (resid 823 through 863 )823 - 863195 - 235
88chain 'A' and (resid 864 through 881 )864 - 881236 - 253
99chain 'A' and (resid 882 through 896 )882 - 896254 - 268

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