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

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Basic information

Entry
Database: PDB / ID: 8bof
TitleCrystal Structure of Ephrin A2 (EphA2) Receptor Protein Kinase with Compound 12
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 / 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-R3L / Ephrin type-A receptor 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.82 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)34,9122
Polymers34,4631
Non-polymers4501
Water1,802100
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration, Also verified by NMR
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area13760 Å2
MethodPISA
Unit cell
Length a, b, c (Å)32.580, 106.430, 40.300
Angle α, β, γ (deg.)90.000, 108.610, 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-R3L / 4-methyl-~{N}-(3-methylphenyl)-3-[(1-methyl-6-pyridin-3-yl-pyrazolo[3,4-d]pyrimidin-4-yl)amino]benzamide


Mass: 449.507 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C26H23N7O / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 100 / 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: 35.98 %
Crystal growTemperature: 291 K / Method: vapor diffusion, sitting drop / pH: 8.5
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 Buffer system 3 pH 8.5 (1M BICINE, 1M Trizma base), 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 Buffer system 3 pH 8.5 (1M BICINE, 1M Trizma base), 0.275 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: 1.82→38.2 Å / Num. obs: 23212 / % possible obs: 98.7 % / Redundancy: 6.78 % / Biso Wilson estimate: 29.73 Å2 / CC1/2: 0.99 / Rrim(I) all: 0.023 / Net I/σ(I): 8.35
Reflection shellResolution: 1.82→1.93 Å / Redundancy: 6.77 % / Mean I/σ(I) obs: 1.03 / Num. unique obs: 3669 / CC1/2: 0.48 / Rrim(I) all: 0.217 / % possible all: 96.8

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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: 1.82→31.03 Å / SU ML: 0.2523 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 24.1123
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2163 1161 5 %
Rwork0.1857 22038 -
obs0.1873 23199 98.87 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 28.83 Å2
Refinement stepCycle: LAST / Resolution: 1.82→31.03 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2127 0 34 100 2261
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0182265
X-RAY DIFFRACTIONf_angle_d1.26773065
X-RAY DIFFRACTIONf_chiral_restr0.0737328
X-RAY DIFFRACTIONf_plane_restr0.0169429
X-RAY DIFFRACTIONf_dihedral_angle_d12.9129881
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.82-1.90.34381400.29462663X-RAY DIFFRACTION96.12
1.9-20.3081450.27522746X-RAY DIFFRACTION99.48
2-2.120.28341460.23742778X-RAY DIFFRACTION99.35
2.12-2.290.22651440.2052727X-RAY DIFFRACTION98.56
2.29-2.520.22071470.18462800X-RAY DIFFRACTION99.53
2.52-2.880.22681450.1822742X-RAY DIFFRACTION99.18
2.88-3.630.20941470.16422795X-RAY DIFFRACTION99.63
3.63-31.030.16351470.15082787X-RAY DIFFRACTION99.16
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)
16.422542668862.012223416640.1694715818313.89876730212-0.5915263215473.191179362360.0116783531356-0.110604454305-0.0828523717441-0.1906504890350.216589468655-0.5560172622620.01371365271290.188701889473-0.2014610947010.3206328474390.015660936221-0.005428424869470.220637839481-0.09250765318880.435032829023-83.061931691-29.284153839781.1249097833
20.9643393138930.5238549724980.2516267919223.39411954436-4.08379556926.80597951197-0.0121717729876-0.2106847077660.1415842162250.2089646546480.2447568491150.210600178299-0.1404131407370.0588458860361-0.1444606969840.2473399330270.00803419054928-0.04108523707830.176501558998-0.0162276446810.298799740176-88.6597102852-27.31284510591.2837074585
30.517730001780.2396691888380.2718173402841.278336870920.1400776072170.312802228323-0.003672860996140.0752525818966-0.1340644104230.03115642421390.0498128891662-0.05025778432360.1053197890060.0521837875477-0.04639327612450.206313118168-0.00170228222280.008614677316390.226565450836-0.01778935969080.161780538057-82.4343052688-16.297539142482.3567312604
41.552267679630.09630171096840.06389492778860.7837815367950.209519987341.847478527230.00703349518064-0.10150214771-0.08452064830510.04940386335470.00242764290297-0.02244244999620.1243859113410.0414597316767-0.0002721572681190.1356864278710.0003404134087850.0008090308167610.1766412126960.007786187528360.155410423051-82.413028711-5.0751002231492.9677400431
51.99070193644-0.1590141920.5363483954341.44618545639-0.3915278245042.34897107369-0.0297206712569-0.1662053693250.06212999459460.0823440841097-0.026721624731-0.0278460275288-0.0537072180931-0.005487798785870.04399928511490.1697557580.0126335212964-0.0008102028114470.163575462366-0.01917243530450.17787300709-82.22060002796.2037323906595.5182336083
63.46605990182-0.2348528746591.052870166411.289749723210.09681580022723.92889044722-0.256657783718-0.5696915261090.1519822687790.2018080085110.110227377879-0.1940138920440.008626464353710.4041270041780.1244696701320.261758304906-0.0167355599962-0.03479320613650.2551711312510.01499449944980.291309721849-63.902818425514.850249041490.6784767861
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 640 )605 - 6401 - 31
22chain 'A' and (resid 641 through 669 )641 - 66932 - 60
33chain 'A' and (resid 670 through 712 )670 - 71261 - 103
44chain 'A' and (resid 713 through 822 )713 - 822104 - 192
55chain 'A' and (resid 823 through 881 )823 - 881193 - 251
66chain 'A' and (resid 882 through 896 )882 - 896252 - 266

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