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- PDB-5ia0: Crystal Structure of Ephrin A2 (EphA2) Receptor Protein Kinase wi... -

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Basic information

Entry
Database: PDB / ID: 5ia0
TitleCrystal Structure of Ephrin A2 (EphA2) Receptor Protein Kinase with alisertib (MLN8237)
ComponentsEphrin type-A receptor 2
KeywordsTRANSFERASE / TYROSINE-PROTEIN KINASE / RECEPTOR / ATP-BINDING
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 / protein localization to plasma membrane / cell chemotaxis / 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 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / 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 / 2-Layer Sandwich / Orthogonal Bundle / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
alisertib / Ephrin type-A receptor 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.948 Å
AuthorsKudlinzki, D. / Linhard, V.L. / Gande, S.L. / Sreeramulu, S. / Saxena, K. / Heinzlmeir, S. / Medard, G. / Kuester, B. / Schwalbe, H.
Funding support Germany, 1items
OrganizationGrant numberCountry
DKTKL590 Germany
CitationJournal: ACS Chem. Biol. / Year: 2016
Title: Chemical Proteomics and Structural Biology Define EPHA2 Inhibition by Clinical Kinase Drugs.
Authors: Heinzlmeir, S. / Kudlinzki, D. / Sreeramulu, S. / Klaeger, S. / Gande, S.L. / Linhard, V. / Wilhelm, M. / Qiao, H. / Helm, D. / Ruprecht, B. / Saxena, K. / Medard, G. / Schwalbe, H. / Kuster, B.
History
DepositionFeb 21, 2016Deposition site: RCSB / Processing site: PDBE
Revision 1.0Nov 9, 2016Provider: repository / Type: Initial release
Revision 1.1Dec 28, 2016Group: Database references
Revision 1.2Jun 12, 2019Group: Data collection / Structure summary
Category: audit_author / database_PDB_rev / database_PDB_rev_record
Item: _audit_author.name
Revision 1.3Jan 10, 2024Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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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
B: Ephrin type-A receptor 2
C: Ephrin type-A receptor 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)106,18726
Polymers103,3893
Non-polymers2,79823
Water9,332518
1
A: Ephrin type-A receptor 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,3548
Polymers34,4631
Non-polymers8917
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Ephrin type-A receptor 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,54011
Polymers34,4631
Non-polymers1,07810
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
C: Ephrin type-A receptor 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,2927
Polymers34,4631
Non-polymers8296
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)57.035, 90.149, 200.590
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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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.: 3 / Fragment: UNP residues 596-900
Source method: isolated from a genetically manipulated source
Details: Ligand ID UNL: unknown ligand alisertib EDO from cryo soaking
Source: (gene. exp.) Homo sapiens (human) / Gene: EPHA2, ECK / Cell line (production host): Sf9 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P29317, receptor protein-tyrosine kinase
#2: Chemical ChemComp-A5B / alisertib


Mass: 518.924 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C27H20ClFN4O4
#3: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 20
Source method: isolated from a genetically manipulated source
Formula: C2H6O2
Details: Ligand ID UNL: unknown ligand alisertib EDO from cryo soaking
Source: (gene. exp.) Homo sapiens (human) / Production host: Spodoptera frugiperda (fall armyworm) / Strain (production host): Sf9 / References: receptor protein-tyrosine kinase
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 518 / Source method: isolated from a natural source / Formula: H2O

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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: 2.49 Å3/Da / Density % sol: 50.68 %
Crystal growTemperature: 291 K / Method: vapor diffusion, sitting drop
Details: 37.5 % MPD_P1k_P3350, 0.3 M Carboxylic Acids, 0.1 M BufferSystem3 pH 8.5

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: BESSY / Beamline: 14.1 / Wavelength: 0.918409 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jul 18, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.918409 Å / Relative weight: 1
ReflectionResolution: 1.948→48.2 Å / Num. obs: 76440 / % possible obs: 99.8 % / Redundancy: 7.41 % / Rpim(I) all: 0.117 / Net I/σ(I): 12.28
Reflection shellResolution: 1.948→2.07 Å / Rpim(I) all: 1.658

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Processing

Software
NameVersionClassification
PHENIX(1.10.1_2155: ???)refinement
XDSdata reduction
PHASERphasing
Cootmodel building
XDSdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1MQB

1mqb


Resolution: 1.948→46.865 Å / SU ML: 0.24 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 24.73 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2249 2100 2.75 %
Rwork0.1937 --
obs0.1942 76426 99.81 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 1.948→46.865 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6367 0 191 518 7076
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0086720
X-RAY DIFFRACTIONf_angle_d0.9779024
X-RAY DIFFRACTIONf_dihedral_angle_d16.3294064
X-RAY DIFFRACTIONf_chiral_restr0.056964
X-RAY DIFFRACTIONf_plane_restr0.0061128
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.9481-1.99350.33091350.32274777X-RAY DIFFRACTION98
1.9935-2.04330.341390.2984924X-RAY DIFFRACTION100
2.0433-2.09860.2381370.27324866X-RAY DIFFRACTION100
2.0986-2.16030.33861380.24824881X-RAY DIFFRACTION100
2.1603-2.230.28481390.23674919X-RAY DIFFRACTION100
2.23-2.30970.26291390.22774930X-RAY DIFFRACTION100
2.3097-2.40220.24611390.22264896X-RAY DIFFRACTION100
2.4022-2.51150.26971400.21724950X-RAY DIFFRACTION100
2.5115-2.6440.24521390.20364930X-RAY DIFFRACTION100
2.644-2.80960.24651400.19744949X-RAY DIFFRACTION100
2.8096-3.02650.26441400.19364976X-RAY DIFFRACTION100
3.0265-3.3310.23961410.18444980X-RAY DIFFRACTION100
3.331-3.81280.1991410.1695013X-RAY DIFFRACTION100
3.8128-4.80290.19211430.15335065X-RAY DIFFRACTION100
4.8029-46.87820.18791500.18555270X-RAY DIFFRACTION100

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