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- PDB-3c7q: Structure of VEGFR2 kinase domain in complex with BIBF1120 -

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Basic information

Entry
Database: PDB / ID: 3c7q
TitleStructure of VEGFR2 kinase domain in complex with BIBF1120
ComponentsVascular endothelial growth factor receptor 2VEGF receptor
KeywordsTRANSFERASE / ALPHA BETA / Angiogenesis / ATP-binding / Developmental protein / Differentiation / Glycoprotein / Host-virus interaction / Immunoglobulin domain / Kinase / Membrane / Nucleotide-binding / Phosphoprotein / Receptor / Transmembrane / Tyrosine-protein kinase
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 / endothelium development / vascular endothelial growth factor receptor-2 signaling pathway / VEGF binds to VEGFR leading to receptor dimerization / 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 / endothelium development / vascular endothelial growth factor receptor-2 signaling pathway / VEGF binds to VEGFR leading to receptor dimerization / endocardium development / vascular wound healing / vascular endothelial growth factor receptor activity / regulation of hematopoietic progenitor cell differentiation / post-embryonic camera-type eye morphogenesis / endothelial cell differentiation / mesenchymal cell proliferation / positive regulation of vasculogenesis / lymph vessel development / positive regulation of BMP signaling pathway / surfactant homeostasis / cell migration involved in sprouting angiogenesis / anchoring junction / epithelial cell maturation / positive regulation of positive chemotaxis / embryonic hemopoiesis / vascular endothelial growth factor signaling pathway / positive regulation of endothelial cell chemotaxis / positive regulation of mesenchymal cell proliferation / positive regulation of mitochondrial depolarization / branching involved in blood vessel morphogenesis / positive regulation of cell migration involved in sprouting angiogenesis / positive regulation of mitochondrial fission / lung alveolus development / positive regulation of stem cell proliferation / positive regulation of nitric-oxide synthase biosynthetic process / sorting endosome / growth factor binding / 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 / Integrin cell surface interactions / vasculogenesis / 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 / transmembrane receptor protein tyrosine kinase activity / positive regulation of endothelial cell migration / VEGFR2 mediated cell proliferation / epithelial cell proliferation / stem cell proliferation / cell surface receptor protein tyrosine kinase signaling pathway / 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 / early endosome / positive regulation of ERK1 and ERK2 cascade / receptor complex / endosome / positive regulation of cell migration / cadherin binding / membrane raft / positive regulation of protein phosphorylation / 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-XIN / Vascular endothelial growth factor receptor 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.1 Å
AuthorsHilberg, F. / Roth, G.J. / Krssak, M. / Kautschitsch, S. / Sommergruber, W. / Tontsch-Grunt, U. / Garin-Chesa, P. / Bader, G. / Zoephel, A. / Quant, J. ...Hilberg, F. / Roth, G.J. / Krssak, M. / Kautschitsch, S. / Sommergruber, W. / Tontsch-Grunt, U. / Garin-Chesa, P. / Bader, G. / Zoephel, A. / Quant, J. / Heckel, A. / Rettig, W.J.
CitationJournal: Cancer Res. / Year: 2008
Title: BIBF 1120: triple angiokinase inhibitor with sustained receptor blockade and good antitumor efficacy.
Authors: Hilberg, F. / Roth, G.J. / Krssak, M. / Kautschitsch, S. / Sommergruber, W. / Tontsch-Grunt, U. / Garin-Chesa, P. / Bader, G. / Zoephel, A. / Quant, J. / Heckel, A. / Rettig, W.J.
History
DepositionFeb 8, 2008Deposition site: RCSB / Processing site: PDBJ
Revision 1.0Dec 23, 2008Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Advisory / Version format compliance
Revision 1.2Oct 25, 2017Group: Advisory / Refinement description / Category: pdbx_unobs_or_zero_occ_atoms / software / Item: _software.name
Revision 1.3Nov 1, 2023Group: Advisory / Data collection ...Advisory / Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / pdbx_unobs_or_zero_occ_atoms / struct_conn / 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_conn.pdbx_leaving_atom_flag / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id
Revision 1.4Nov 15, 2023Group: Data collection / Category: chem_comp_atom / chem_comp_bond / Item: _chem_comp_atom.atom_id / _chem_comp_bond.atom_id_2

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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)37,5777
Polymers36,5571
Non-polymers1,0206
Water3,711206
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)38.250, 94.440, 96.220
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 Vascular endothelial growth factor receptor 2 / VEGF receptor / VEGFR-2 / Kinase insert domain receptor / Protein-tyrosine kinase receptor Flk-1 / CD309 antigen


Mass: 36556.988 Da / Num. of mol.: 1 / Fragment: kinase domain
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: KDR, FLK1 / Cell line (production host): SF9 / Production host: Spodoptera frugiperda (fall armyworm) / Strain (production host): High5
References: UniProt: P35968, receptor protein-tyrosine kinase
#2: Chemical
ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: SO4
#3: Chemical ChemComp-XIN / methyl (3Z)-3-{[(4-{methyl[(4-methylpiperazin-1-yl)acetyl]amino}phenyl)amino](phenyl)methylidene}-2-oxo-2,3-dihydro-1H-indole-6-carboxylate / Nintedanib


Mass: 539.625 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C31H33N5O4 / Comment: medication*YM
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 206 / Source method: isolated from a natural source / Formula: H2O
Sequence detailsTHERE ARE DELETIONS T940-A991 AND RESIDUE NUMBERS 940-991 ARE SIMPLY SKIPPED.

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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: 2.38 Å3/Da / Density % sol: 48.25 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 7.4
Details: 0.1M HEPES, 2.1M Ammonium Sulphate, 3% PEG MME 550, 10mM Beta-Mercaptoethanol, pH 7.4, VAPOR DIFFUSION, HANGING DROP, temperature 277K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06SA / Wavelength: 0.9799 Å
DetectorType: MARMOSAIC 225 mm CCD / Detector: CCD / Date: Dec 15, 2006
RadiationMonochromator: Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9799 Å / Relative weight: 1
ReflectionResolution: 2→30 Å / Num. obs: 23933 / % possible obs: 98.4 % / Observed criterion σ(I): -3 / Biso Wilson estimate: 32.839 Å2 / Rmerge(I) obs: 0.087 / Net I/σ(I): 9.91
Reflection shellResolution: 2→2.1 Å / Rmerge(I) obs: 0.559 / Mean I/σ(I) obs: 2 / Num. measured obs: 8152 / Num. unique obs: 2948 / % possible all: 91.2

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Phasing

PhasingMethod: molecular replacement
Phasing MR
Highest resolutionLowest resolution
Rotation3.5 Å28.54 Å
Translation3.5 Å28.54 Å

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Processing

Software
NameVersionClassificationNB
XSCALEdata scaling
MOLREPphasing
REFMACrefinement
PDB_EXTRACT3.004data extraction
MAR345data collection
XDSdata reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1VR2

1vr2


Resolution: 2.1→28.54 Å / Cor.coef. Fo:Fc: 0.938 / Cor.coef. Fo:Fc free: 0.906 / SU B: 7.47 / SU ML: 0.194 / TLS residual ADP flag: LIKELY RESIDUAL / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.243 / ESU R Free: 0.215 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.279 1050 5 %RANDOM
Rwork0.217 ---
obs0.221 19934 100 %-
all-19934 --
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK
Displacement parametersBiso mean: 24.366 Å2
Baniso -1Baniso -2Baniso -3
1--0.87 Å20 Å20 Å2
2--2.84 Å20 Å2
3----1.97 Å2
Refinement stepCycle: LAST / Resolution: 2.1→28.54 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2362 0 65 206 2633
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0140.0222455
X-RAY DIFFRACTIONr_bond_other_d0.0010.021694
X-RAY DIFFRACTIONr_angle_refined_deg1.6332.0033323
X-RAY DIFFRACTIONr_angle_other_deg0.99734090
X-RAY DIFFRACTIONr_dihedral_angle_1_deg8.3115288
X-RAY DIFFRACTIONr_dihedral_angle_2_deg36.28422.991107
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.38915405
X-RAY DIFFRACTIONr_dihedral_angle_4_deg17.0381518
X-RAY DIFFRACTIONr_chiral_restr0.1140.2350
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.022652
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02515
X-RAY DIFFRACTIONr_nbd_refined0.2060.2561
X-RAY DIFFRACTIONr_nbd_other0.20.21787
X-RAY DIFFRACTIONr_nbtor_refined0.1850.21163
X-RAY DIFFRACTIONr_nbtor_other0.0890.21255
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1810.2149
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.1970.225
X-RAY DIFFRACTIONr_symmetry_vdw_other0.220.251
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.2670.215
X-RAY DIFFRACTIONr_mcbond_it1.1841.51870
X-RAY DIFFRACTIONr_mcbond_other0.1551.5585
X-RAY DIFFRACTIONr_mcangle_it1.35422325
X-RAY DIFFRACTIONr_scbond_it1.78931220
X-RAY DIFFRACTIONr_scangle_it2.5294.5998
LS refinement shellResolution: 2.1→2.154 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.402 76 -
Rwork0.277 1447 -
all-1523 -
obs-1447 100 %
Refinement TLS params.Method: refined / Origin x: 24.236 Å / Origin y: 56.675 Å / Origin z: 24.854 Å
111213212223313233
T-0.0329 Å20.0304 Å2-0.0095 Å2--0.0264 Å2-0.0198 Å2---0.0113 Å2
L0.3213 °20.0304 °2-0.3528 °2-0.2557 °20.2771 °2--1.2602 °2
S0.0005 Å °0.0572 Å °-0.0733 Å °0.0138 Å °-0.0414 Å °0.0071 Å °-0.0557 Å °-0.1179 Å °0.0409 Å °

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