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- PDB-3ewh: Crystal structure of the VEGFR2 kinase domain in complex with a p... -

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Basic information

Entry
Database: PDB / ID: 3ewh
TitleCrystal structure of the VEGFR2 kinase domain in complex with a pyridyl-pyrimidine benzimidazole inhibitor
Componentsvascular endothelial growth factor receptor 2
KeywordsTRANSFERASE / angiogenesis / receptor tyrosine kinase / DFG-out
Function / homology
Function and homology information


cellular response to hydrogen sulfide / blood vessel endothelial cell differentiation / regulation of bone development / Signaling by membrane-tethered fusions of PDGFRA or PDGFRB / post-embryonic camera-type eye morphogenesis / 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 ...cellular response to hydrogen sulfide / blood vessel endothelial cell differentiation / regulation of bone development / Signaling by membrane-tethered fusions of PDGFRA or PDGFRB / post-embryonic camera-type eye morphogenesis / 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 / positive regulation of vasculogenesis / endothelial cell differentiation / lymph vessel development / mesenchymal cell proliferation / positive regulation of BMP signaling pathway / surfactant homeostasis / cell migration involved in sprouting angiogenesis / positive regulation of mesenchymal cell proliferation / epithelial cell maturation / anchoring junction / positive regulation of positive chemotaxis / embryonic hemopoiesis / vascular endothelial growth factor signaling pathway / positive regulation of endothelial cell chemotaxis / lung alveolus development / positive regulation of cell migration involved in sprouting angiogenesis / branching involved in blood vessel morphogenesis / positive regulation of mitochondrial fission / positive regulation of mitochondrial depolarization / positive regulation of stem cell proliferation / regulation of MAPK cascade / positive regulation of nitric-oxide synthase biosynthetic process / growth factor binding / sorting endosome / positive regulation of focal adhesion assembly / positive regulation of macroautophagy / semaphorin-plexin signaling pathway / cell fate commitment / positive regulation of blood vessel endothelial cell migration / cellular response to vascular endothelial growth factor stimulus / Integrin cell surface interactions / vasculogenesis / vascular endothelial growth factor receptor signaling pathway / negative regulation of endothelial cell apoptotic process / coreceptor activity / calcium ion homeostasis / peptidyl-tyrosine autophosphorylation / cell surface receptor protein tyrosine kinase signaling pathway / ovarian follicle development / positive regulation of endothelial cell proliferation / transmembrane receptor protein tyrosine kinase activity / positive regulation of endothelial cell migration / epithelial cell proliferation / VEGFR2 mediated cell proliferation / stem cell proliferation / Hsp90 protein binding / receptor protein-tyrosine kinase / VEGFA-VEGFR2 Pathway / peptidyl-tyrosine phosphorylation / positive regulation of angiogenesis / integrin binding / cell migration / cell junction / regulation of cell shape / protein tyrosine kinase activity / angiogenesis / negative regulation of neuron apoptotic process / protein autophosphorylation / positive regulation of MAPK cascade / positive regulation of ERK1 and ERK2 cascade / early endosome / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / 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 / 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 / VEGFR1-3, N-terminal Ig-like domain / VEGFR-1-like, immunoglobulin-like domain / Tyrosine-protein kinase, receptor class III, conserved site / Receptor tyrosine kinase class III signature. / Immunoglobulin domain / Immunoglobulin ...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 / VEGFR1-3, N-terminal Ig-like domain / VEGFR-1-like, immunoglobulin-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. / Tyrosine-protein kinase, active site / Immunoglobulin subtype / Immunoglobulin / Serine-threonine/tyrosine-protein kinase, catalytic domain / Protein tyrosine and serine/threonine kinase / 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-K11 / Vascular endothelial growth factor receptor 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 1.6 Å
AuthorsWhittington, D.A. / Long, A.M. / Rose, P. / Gu, Y. / Zhao, H.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2009
Title: Pyridyl-pyrimidine benzimidazole derivatives as potent, selective, and orally bioavailable inhibitors of Tie-2 kinase.
Authors: Cee, V.J. / Cheng, A.C. / Romero, K. / Bellon, S. / Mohr, C. / Whittington, D.A. / Bak, A. / Bready, J. / Caenepeel, S. / Coxon, A. / Deak, H.L. / Fretland, J. / Gu, Y. / Hodous, B.L. / ...Authors: Cee, V.J. / Cheng, A.C. / Romero, K. / Bellon, S. / Mohr, C. / Whittington, D.A. / Bak, A. / Bready, J. / Caenepeel, S. / Coxon, A. / Deak, H.L. / Fretland, J. / Gu, Y. / Hodous, B.L. / Huang, X. / Kim, J.L. / Lin, J. / Long, A.M. / Nguyen, H. / Olivieri, P.R. / Patel, V.F. / Wang, L. / Zhou, Y. / Hughes, P. / Geuns-Meyer, S.
History
DepositionOct 15, 2008Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 25, 2009Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Aug 23, 2017Group: Refinement description / Source and taxonomy / Category: entity_src_gen / software
Revision 1.3Oct 20, 2021Group: Database references / Derived calculations / Category: database_2 / struct_ref_seq_dif / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id
Revision 1.4Dec 27, 2023Group: Data collection / Category: chem_comp_atom / chem_comp_bond

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: vascular endothelial growth factor receptor 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,7143
Polymers36,1251
Non-polymers5902
Water4,828268
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)41.319, 84.380, 47.404
Angle α, β, γ (deg.)90.00, 99.33, 90.00
Int Tables number4
Space group name H-MP1211

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Components

#1: Protein vascular endothelial growth factor receptor 2 / VEGFR-2 / Kinase insert domain receptor / Protein-tyrosine kinase receptor Flk-1 / CD309 antigen


Mass: 36124.629 Da / Num. of mol.: 1 / Fragment: UNP residues 815-939, 990-1171 / Mutation: C817A, V916T, E990V
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: KDR, FLK1 / Production host: Trichoplusia ni (cabbage looper)
References: UniProt: P35968, receptor protein-tyrosine kinase
#2: Chemical ChemComp-K11 / N-[4-({3-[2-(methylamino)pyrimidin-4-yl]pyridin-2-yl}oxy)naphthalen-1-yl]-6-(trifluoromethyl)-1H-benzimidazol-2-amine


Mass: 527.500 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C28H20F3N7O
#3: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6O2
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 268 / 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: 2.26 Å3/Da / Density % sol: 45.51 %
Crystal growTemperature: 277 K / Method: vapor diffusion / pH: 8
Details: PEG 5000 MME, HEPES, ammonium sulfate, sodium chloride, isopropanol, beta-mercaptoethanol , pH 8.0, VAPOR DIFFUSION, temperature 277K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU FR-E SUPERBRIGHT / Wavelength: 1.5418 Å
DetectorType: RIGAKU RAXIS IV++ / Detector: IMAGE PLATE / Date: Aug 22, 2006
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 1.6→30 Å / Num. obs: 39565 / % possible obs: 93.3 % / Observed criterion σ(I): -3 / Redundancy: 3.1 % / Biso Wilson estimate: 23.8 Å2 / Rmerge(I) obs: 0.051 / Χ2: 1.055 / Net I/σ(I): 22.3
Reflection shellResolution: 1.6→1.66 Å / Redundancy: 1.7 % / Rmerge(I) obs: 0.266 / Mean I/σ(I) obs: 2.5 / Num. unique all: 2012 / Χ2: 1.06 / % possible all: 47.7

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Processing

Software
NameVersionClassificationNB
SCALEPACKdata scaling
REFMACrefinement
PDB_EXTRACT1.401data extraction
CrystalCleardata collection
DENZOdata reduction
AMoREphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.6→21.1 Å / Cor.coef. Fo:Fc: 0.951 / Cor.coef. Fo:Fc free: 0.938 / SU B: 1.736 / SU ML: 0.063 / SU R Cruickshank DPI: 0.11 / Cross valid method: THROUGHOUT / ESU R Free: 0.105
RfactorNum. reflection% reflectionSelection details
Rfree0.234 1973 5 %RANDOM
Rwork0.206 ---
all0.208 42366 --
obs-39541 93.33 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 19.4 Å2
Baniso -1Baniso -2Baniso -3
1-0.15 Å20 Å2-0.41 Å2
2---0.31 Å20 Å2
3---0.03 Å2
Refinement stepCycle: LAST / Resolution: 1.6→21.1 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2424 0 43 268 2735
Refine LS restraints
Refine-IDTypeDev idealNumberWeight
X-RAY DIFFRACTIONr_bond_refined_d0.00725330.022
X-RAY DIFFRACTIONr_angle_refined_deg1.03534241.978
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.2762965
X-RAY DIFFRACTIONr_dihedral_angle_2_deg30.80411822.881
X-RAY DIFFRACTIONr_dihedral_angle_3_deg11.6543315
X-RAY DIFFRACTIONr_dihedral_angle_4_deg17.9682015
X-RAY DIFFRACTIONr_chiral_restr0.0743610.2
X-RAY DIFFRACTIONr_gen_planes_refined0.00319260.02
X-RAY DIFFRACTIONr_nbd_refined0.18212260.2
X-RAY DIFFRACTIONr_nbtor_refined0.30517280.2
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.0962400.2
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.164580.2
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.076230.2
X-RAY DIFFRACTIONr_mcbond_it0.79915492
X-RAY DIFFRACTIONr_mcangle_it1.24424063
X-RAY DIFFRACTIONr_scbond_it1.27811543
X-RAY DIFFRACTIONr_scangle_it1.93710184.5
LS refinement shellResolution: 1.6→1.64 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.601 67 -
Rwork0.566 1277 -
obs--42.86 %

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