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- PDB-3vnt: Crystal Structure of the Kinase domain of Human VEGFR2 with a [1,... -

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Basic information

Entry
Database: PDB / ID: 3vnt
TitleCrystal Structure of the Kinase domain of Human VEGFR2 with a [1,3]thiazolo[5,4-b]pyridine derivative
ComponentsVascular endothelial growth factor receptor 2
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / vegfr2 / kinase domain / Tyrosin-protein kinase / TRANSFERASE-TRANSFERASE INHIBITOR complex
Function / homology
Function and homology information


positive regulation of nitric oxide-cGMP mediated signal transduction / blood vessel endothelial cell differentiation / regulation of bone development / cellular response to hydrogen sulfide / Signaling by membrane-tethered fusions of PDGFRA or PDGFRB / Neurophilin interactions with VEGF and VEGFR / vascular endothelial growth factor binding / vascular endothelial growth factor receptor-2 signaling pathway / endothelium development / VEGF binds to VEGFR leading to receptor dimerization ...positive regulation of nitric oxide-cGMP mediated signal transduction / blood vessel endothelial cell differentiation / regulation of bone development / cellular response to hydrogen sulfide / Signaling by membrane-tethered fusions of PDGFRA or PDGFRB / Neurophilin interactions with VEGF and VEGFR / vascular endothelial growth factor binding / vascular endothelial growth factor receptor-2 signaling pathway / endothelium development / VEGF binds to VEGFR leading to receptor dimerization / endocardium development / vascular wound healing / vascular endothelial growth factor receptor activity / endothelial cell differentiation / regulation of hematopoietic progenitor cell differentiation / post-embryonic camera-type eye morphogenesis / lymph vessel development / mesenchymal cell proliferation / positive regulation of vasculogenesis / positive regulation of BMP signaling pathway / surfactant homeostasis / cell migration involved in sprouting angiogenesis / epithelial cell maturation / positive regulation of positive chemotaxis / positive regulation of endothelial cell chemotaxis / positive regulation of cell migration involved in sprouting angiogenesis / embryonic hemopoiesis / positive regulation of mesenchymal cell proliferation / anchoring junction / vascular endothelial growth factor signaling pathway / lung alveolus development / growth factor binding / branching involved in blood vessel morphogenesis / positive regulation of mitochondrial fission / positive regulation of stem cell proliferation / positive regulation of mitochondrial depolarization / sorting endosome / semaphorin-plexin signaling pathway / regulation of MAPK cascade / positive regulation of macroautophagy / cellular response to vascular endothelial growth factor stimulus / positive regulation of blood vessel endothelial cell migration / positive regulation of focal adhesion assembly / cell fate commitment / vascular endothelial growth factor receptor signaling pathway / Integrin cell surface interactions / negative regulation of endothelial cell apoptotic process / vasculogenesis / calcium ion homeostasis / ovarian follicle development / coreceptor activity / positive regulation of endothelial cell proliferation / transmembrane receptor protein tyrosine kinase activity / positive regulation of endothelial cell migration / cell surface receptor protein tyrosine kinase signaling pathway / peptidyl-tyrosine phosphorylation / VEGFR2 mediated cell proliferation / epithelial cell proliferation / stem cell proliferation / Hsp90 protein binding / receptor protein-tyrosine kinase / VEGFA-VEGFR2 Pathway / integrin binding / positive regulation of protein phosphorylation / positive regulation of angiogenesis / cell junction / cell migration / regulation of cell shape / protein autophosphorylation / protein tyrosine kinase activity / High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells / angiogenesis / negative regulation of neuron apoptotic process / early endosome / positive regulation of ERK1 and ERK2 cascade / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / receptor complex / positive regulation of MAPK cascade / endosome / positive regulation of cell migration / cadherin binding / membrane raft / negative regulation of gene expression / external side of plasma membrane / positive regulation of cell population proliferation / endoplasmic reticulum / Golgi apparatus / 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. ...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. / Immunoglobulin subtype / Immunoglobulin / 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 / 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-0JA / Vascular endothelial growth factor receptor 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.64 Å
AuthorsOki, H.
CitationJournal: J.Med.Chem. / Year: 2012
Title: Design and synthesis of novel DFG-out RAF/vascular endothelial growth factor receptor 2 (VEGFR2) inhibitors. 1. Exploration of [5,6]-fused bicyclic scaffolds
Authors: Okaniwa, M. / Hirose, M. / Imada, T. / Ohashi, T. / Hayashi, Y. / Miyazaki, T. / Arita, T. / Yabuki, M. / Kakoi, K. / Kato, J. / Takagi, T. / Kawamoto, T. / Yao, S. / Sumita, A. / Tsutsumi, ...Authors: Okaniwa, M. / Hirose, M. / Imada, T. / Ohashi, T. / Hayashi, Y. / Miyazaki, T. / Arita, T. / Yabuki, M. / Kakoi, K. / Kato, J. / Takagi, T. / Kawamoto, T. / Yao, S. / Sumita, A. / Tsutsumi, S. / Tottori, T. / Oki, H. / Sang, B.C. / Yano, J. / Aertgeerts, K. / Yoshida, S. / Ishikawa, T.
History
DepositionJan 17, 2012Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Apr 11, 2012Provider: repository / Type: Initial release
Revision 1.1Aug 7, 2013Group: Database references
Revision 1.2Mar 20, 2024Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_struct_special_symmetry / 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

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)37,0875
Polymers36,3531
Non-polymers7344
Water4,558253
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)135.615, 56.618, 51.819
Angle α, β, γ (deg.)90.00, 94.88, 90.00
Int Tables number5
Space group name H-MC121
Components on special symmetry positions
IDModelComponents
11A-3090-

HOH

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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: 36352.875 Da / Num. of mol.: 1 / Fragment: UNP residues 806-1171 / Mutation: truncated residues 940-989
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: KDR, FLK1, VEGFR2 / Plasmid: pFastBac / Production host: Spodoptera frugiperda (fall armyworm) / Strain (production host): Sf9
References: UniProt: P35968, receptor protein-tyrosine kinase
#2: Chemical ChemComp-0JA / 2-chloro-3-(1-cyanocyclopropyl)-N-[5-({2-[(cyclopropylcarbonyl)amino][1,3]thiazolo[5,4-b]pyridin-5-yl}oxy)-2-fluorophenyl]benzamide


Mass: 547.988 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C27H19ClFN5O3S
#3: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C2H6O2
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 253 / 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: 2.73 Å3/Da / Density % sol: 54.88 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop
Details: 100mM HEPES, 880-1440mM tri-sodium citrate, pH 7.0-8.0, vapor diffusion, sitting drop, temperature 293K
PH range: 7.0-8.0

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.2 / Wavelength: 0.992 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Nov 16, 2010
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.992 Å / Relative weight: 1
ReflectionResolution: 1.64→50 Å / Num. obs: 46806 / % possible obs: 97.2 % / Redundancy: 4.1 % / Rmerge(I) obs: 0.052 / Net I/σ(I): 15.4
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsDiffraction-ID% possible all
1.64-1.673.90.786195.6
1.67-1.74.10.669196
1.7-1.734.20.605195.9
1.73-1.774.30.482196.3
1.77-1.814.30.385196.2
1.81-1.854.30.32196.7
1.85-1.894.30.255196.7
1.89-1.944.30.195196.7
1.94-24.30.154197.2
2-2.074.30.122197.1
2.07-2.144.20.105197.4
2.14-2.234.20.084197.6
2.23-2.334.20.074197.7
2.33-2.454.20.066197.8
2.45-2.64.10.06198
2.6-2.84.10.052198.1
2.8-3.093.90.046198.4
3.09-3.533.80.038198.5
3.53-4.453.80.033197.9
4.45-503.90.032197.8

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassificationNB
SCALEPACKdata scaling
MOLREPphasing
REFMACrefmac_5.2.0019refinement
PDB_EXTRACT3.1data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.64→37.33 Å / Cor.coef. Fo:Fc: 0.974 / Cor.coef. Fo:Fc free: 0.962 / Occupancy max: 1 / Occupancy min: 0.5 / SU B: 3.037 / SU ML: 0.051 / Cross valid method: THROUGHOUT / ESU R: 0.093 / ESU R Free: 0.081 / Stereochemistry target values: MAXIMUM LIKELIHOOD
RfactorNum. reflection% reflectionSelection details
Rfree0.19203 2371 5.1 %RANDOM
Rwork0.15147 ---
obs0.15346 44402 97.07 %-
all-46773 --
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: BABINET MODEL WITH MASK
Displacement parametersBiso mean: 29.926 Å2
Baniso -1Baniso -2Baniso -3
1-1.91 Å20 Å20.22 Å2
2---0.52 Å20 Å2
3----1.35 Å2
Refinement stepCycle: LAST / Resolution: 1.64→37.33 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2422 0 50 253 2725
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0080.0222571
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.1721.9863478
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.3025309
X-RAY DIFFRACTIONr_dihedral_angle_2_deg32.67922.957115
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.34115449
X-RAY DIFFRACTIONr_dihedral_angle_4_deg20.191520
X-RAY DIFFRACTIONr_chiral_restr0.0790.2366
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.021994
X-RAY DIFFRACTIONr_gen_planes_other
X-RAY DIFFRACTIONr_nbd_refined0.190.21161
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined0.3090.21762
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1390.2218
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.2060.237
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.1080.218
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it2.62821565
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it3.87132460
X-RAY DIFFRACTIONr_scbond_it6.59751158
X-RAY DIFFRACTIONr_scangle_it9.31481010
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.639→1.681 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.289 176 -
Rwork0.173 3154 -
obs--94.87 %
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)
10.17-0.02430.18380.6997-0.09760.3136-0.02070.04070.02820.10220.0088-0.05120.0272-0.00510.0119-0.00930.0021-0.00650.00210.00660.012833.7462-30.2654-8.7863
20.25530.14590.12410.08340.07090.06040.0022-0.04470.017-0.0598-0.0319-0.00360.04460.0320.0297-0.01080.00420.00410.02390.01330.017818.4422-28.9335-29.15
32.6011-2.4556-2.2123.02142.12891.8834-0.05790.1750.0822-0.04430.02280.03230.1975-0.33240.0351-0.06250.00540.00160.05640.03150.039626.7574-28.6107-14.3362
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A813 - 920
2X-RAY DIFFRACTION2A921 - 1168
3X-RAY DIFFRACTION3A2001

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