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- PDB-5ew3: Human Vascular Endothelial Growth Factor Receptor 2 (KDR) Kinase ... -

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Basic information

Entry
Database: PDB / ID: 5ew3
TitleHuman Vascular Endothelial Growth Factor Receptor 2 (KDR) Kinase Domain in complex with AAL993
ComponentsVascular endothelial growth factor receptor 2
KeywordsTRANSFERASE / kdr / kinase domain / ATP-binding site / VEGFR2 inhibitors
Function / homology
Function and homology information


blood vessel endothelial cell differentiation / cellular response to hydrogen sulfide / regulation of bone development / Signaling by membrane-tethered fusions of PDGFRA or PDGFRB / vascular endothelial growth factor binding / Neurophilin interactions with VEGF and VEGFR / vascular endothelial growth factor receptor-2 signaling pathway / VEGF binds to VEGFR leading to receptor dimerization / endothelium development / endocardium development ...blood vessel endothelial cell differentiation / cellular response to hydrogen sulfide / regulation of bone development / Signaling by membrane-tethered fusions of PDGFRA or PDGFRB / vascular endothelial growth factor binding / Neurophilin interactions with VEGF and VEGFR / vascular endothelial growth factor receptor-2 signaling pathway / VEGF binds to VEGFR leading to receptor dimerization / endothelium development / endocardium development / vascular wound healing / regulation of hematopoietic progenitor cell differentiation / vascular endothelial growth factor receptor activity / post-embryonic camera-type eye morphogenesis / endothelial cell differentiation / positive regulation of vasculogenesis / mesenchymal cell proliferation / lymph vessel development / positive regulation of BMP signaling pathway / surfactant homeostasis / cell migration involved in sprouting angiogenesis / epithelial cell maturation / anchoring junction / positive regulation of positive chemotaxis / embryonic hemopoiesis / vascular endothelial growth factor signaling pathway / positive regulation of mesenchymal cell proliferation / positive regulation of endothelial cell chemotaxis / branching involved in blood vessel morphogenesis / positive regulation of cell migration involved in sprouting angiogenesis / positive regulation of mitochondrial fission / positive regulation of mitochondrial depolarization / lung alveolus development / positive regulation of stem cell proliferation / positive regulation of nitric-oxide synthase biosynthetic process / growth factor binding / sorting endosome / positive regulation of focal adhesion assembly / regulation of MAPK cascade / semaphorin-plexin signaling pathway / : / positive regulation of macroautophagy / positive regulation of blood vessel endothelial cell migration / cellular response to vascular endothelial growth factor stimulus / cell fate commitment / calcium ion homeostasis / vasculogenesis / Integrin cell surface interactions / vascular endothelial growth factor receptor signaling pathway / coreceptor activity / negative regulation of endothelial cell apoptotic process / peptidyl-tyrosine autophosphorylation / ovarian follicle development / positive regulation of endothelial cell proliferation / cell surface receptor protein tyrosine kinase signaling pathway / positive regulation of endothelial cell migration / transmembrane receptor protein tyrosine kinase activity / VEGFR2 mediated cell proliferation / epithelial cell proliferation / stem cell proliferation / Hsp90 protein binding / receptor protein-tyrosine kinase / VEGFA-VEGFR2 Pathway / peptidyl-tyrosine phosphorylation / positive regulation of angiogenesis / cell migration / integrin binding / cell junction / regulation of cell shape / protein tyrosine kinase activity / angiogenesis / negative regulation of neuron apoptotic process / positive regulation of MAPK cascade / protein autophosphorylation / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / positive regulation of ERK1 and ERK2 cascade / early endosome / receptor complex / endosome / positive regulation of cell migration / cadherin binding / positive regulation of protein phosphorylation / membrane raft / external side of plasma membrane / negative regulation of gene expression / positive regulation of cell population proliferation / negative regulation of apoptotic process / Golgi apparatus / endoplasmic reticulum / extracellular region / ATP binding / identical protein binding / nucleus / plasma membrane
Similarity search - Function
Vascular endothelial growth factor receptor 2 (VEGFR2) / VEGFR-2, transmembrane domain / VEGFR-2 Transmembrane domain / Vascular endothelial growth factor receptor 1-like, Ig-like domain / Tyrosine-protein kinase, receptor class III, conserved site / Receptor tyrosine kinase class III signature. / Immunoglobulin domain / Immunoglobulin / Immunoglobulin domain / Immunoglobulin I-set ...Vascular endothelial growth factor receptor 2 (VEGFR2) / VEGFR-2, transmembrane domain / VEGFR-2 Transmembrane domain / Vascular endothelial growth factor receptor 1-like, Ig-like domain / Tyrosine-protein kinase, receptor class III, conserved site / Receptor tyrosine kinase class III signature. / Immunoglobulin domain / Immunoglobulin / Immunoglobulin domain / Immunoglobulin I-set / Immunoglobulin I-set domain / Immunoglobulin subtype 2 / Immunoglobulin C-2 Type / Tyrosine-protein kinase, catalytic domain / Tyrosine kinase, catalytic domain / Tyrosine protein kinases specific active-site signature. / Immunoglobulin subtype / Immunoglobulin / Tyrosine-protein kinase, active site / Protein tyrosine and serine/threonine kinase / Serine-threonine/tyrosine-protein kinase, catalytic domain / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Ig-like domain profile. / Immunoglobulin-like domain / Immunoglobulin-like domain superfamily / 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
Chem-5T2 / Vascular endothelial growth factor receptor 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.5 Å
AuthorsStark, W. / Goepfert, A.
Citation
Journal: J.Med.Chem. / Year: 2016
Title: A Novel Potent Oral Series of VEGFR2 Inhibitors Abrogate Tumor Growth by Inhibiting Angiogenesis.
Authors: Bold, G. / Schnell, C. / Furet, P. / McSheehy, P. / Bruggen, J. / Mestan, J. / Manley, P.W. / Druckes, P. / Burglin, M. / Durler, U. / Loretan, J. / Reuter, R. / Wartmann, M. / Theuer, A. / ...Authors: Bold, G. / Schnell, C. / Furet, P. / McSheehy, P. / Bruggen, J. / Mestan, J. / Manley, P.W. / Druckes, P. / Burglin, M. / Durler, U. / Loretan, J. / Reuter, R. / Wartmann, M. / Theuer, A. / Bauer-Probst, B. / Martiny-Baron, G. / Allegrini, P. / Goepfert, A. / Wood, J. / Littlewood-Evans, A.
#1: Journal: Biochimica et Biophysica Acta, Proteins and Proteomics
Year: 2004
Title: Advances in the structural biology, design and clinical development of VEGF-R kinase inhibitors for the treatment of angiogenesis
Authors: Manley, P.W. / Bold, G. / Bruggen, J. / Fendrich, G. / Furet, P. / Mestan, J. / Schnell, C. / Stolz, B. / Meyer, T. / Meyhack, B. / Stark, W. / Strauss, A. / Wood, J.
History
DepositionNov 20, 2015Deposition site: RCSB / Processing site: PDBE
Revision 1.0Dec 16, 2015Provider: repository / Type: Initial release
Revision 1.1Jan 27, 2016Group: Database references
Revision 1.2Jan 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

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Assembly

Deposited unit
A: Vascular endothelial growth factor receptor 2
B: Vascular endothelial growth factor receptor 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)73,1324
Polymers72,3902
Non-polymers7432
Water1,36976
1
A: Vascular endothelial growth factor receptor 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,5662
Polymers36,1951
Non-polymers3711
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Vascular endothelial growth factor receptor 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,5662
Polymers36,1951
Non-polymers3711
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)67.500, 55.760, 89.760
Angle α, β, γ (deg.)90.000, 92.280, 90.000
Int Tables number4
Space group name H-MP1211

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Components

#1: Protein Vascular endothelial growth factor receptor 2 / VEGFR-2 / Fetal liver kinase 1 / FLK-1 / Kinase insert domain receptor / KDR / Protein-tyrosine ...VEGFR-2 / Fetal liver kinase 1 / FLK-1 / Kinase insert domain receptor / KDR / Protein-tyrosine kinase receptor flk-1


Mass: 36194.762 Da / Num. of mol.: 2 / Fragment: kinase domain, residues 806-1171 / Mutation: E990V
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: KDR, FLK1, VEGFR2 / Plasmid: pVL1393 / Cell line (production host): SF9 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P35968, receptor protein-tyrosine kinase
#2: Chemical ChemComp-5T2 / 2-(pyridin-4-ylmethylamino)-~{N}-[3-(trifluoromethyl)phenyl]benzamide


Mass: 371.356 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C20H16F3N3O
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 76 / 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: 2.33 Å3/Da / Density % sol: 47.25 %
Crystal growTemperature: 290 K / Method: vapor diffusion, hanging drop / pH: 6.5
Details: 0.1M MES pH6.5, 8% w/v PEG 8000, 0.02M LITHIUM ACETATE

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06SA / Wavelength: 0.8727 Å
DetectorType: MAR scanner 345 mm plate / Detector: IMAGE PLATE / Date: Oct 3, 2002
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.8727 Å / Relative weight: 1
ReflectionResolution: 2.5→100 Å / Num. all: 23547 / Num. obs: 23229 / % possible obs: 98.9 % / Redundancy: 3.37 % / Rmerge(I) obs: 0.081 / Net I/σ(I): 17.05
Reflection shellResolution: 2.5→2.59 Å / Rmerge(I) obs: 0.582 / % possible all: 98.9

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassification
DENZOdata reduction
SCALEPACKdata scaling
AMoREphasing
BUSTER-TNTrefinement
PDB_EXTRACT3.15data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1vr2

1vr2


Resolution: 2.5→19.68 Å / Cor.coef. Fo:Fc: 0.9287 / Cor.coef. Fo:Fc free: 0.9109 / SU R Cruickshank DPI: 0.503 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.473 / SU Rfree Blow DPI: 0.271 / SU Rfree Cruickshank DPI: 0.278
RfactorNum. reflection% reflectionSelection details
Rfree0.2535 665 2.88 %RANDOM
Rwork0.2184 ---
obs0.2194 23051 98.94 %-
Displacement parametersBiso max: 167.08 Å2 / Biso mean: 62.95 Å2 / Biso min: 27.07 Å2
Baniso -1Baniso -2Baniso -3
1--0.4887 Å20 Å20.1703 Å2
2---1.5698 Å20 Å2
3---2.0584 Å2
Refinement stepCycle: final / Resolution: 2.5→19.68 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4324 0 54 76 4454
Biso mean--45.79 56.14 -
Num. residues----540
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d1559SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes90HARMONIC2
X-RAY DIFFRACTIONt_gen_planes645HARMONIC5
X-RAY DIFFRACTIONt_it4486HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion559SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact4891SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d4486HARMONIC20.008
X-RAY DIFFRACTIONt_angle_deg6057HARMONIC20.99
X-RAY DIFFRACTIONt_omega_torsion2.51
X-RAY DIFFRACTIONt_other_torsion15.75
LS refinement shellResolution: 2.5→2.61 Å / Total num. of bins used: 12
RfactorNum. reflection% reflection
Rfree0.2653 90 3.27 %
Rwork0.2179 2666 -
all0.2193 2756 -
obs--98.94 %

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