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

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Basic information

Entry
Database: PDB / ID: 3vhk
TitleCrystal structure of the VEGFR2 kinase domain in complex with a back pocket binder
ComponentsVascular endothelial growth factor receptor 2
KeywordsTRANSFERASE / vegfr2 / kinase domain / complex
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 / 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 ...cellular response to hydrogen sulfide / blood vessel endothelial cell differentiation / 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 / vascular endothelial growth factor receptor activity / regulation of hematopoietic progenitor cell differentiation / post-embryonic camera-type eye morphogenesis / 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 / 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 / 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 / lung alveolus development / positive regulation of stem cell proliferation / : / sorting endosome / growth factor binding / positive regulation of focal adhesion assembly / positive regulation of macroautophagy / regulation of MAPK cascade / semaphorin-plexin signaling pathway / positive regulation of blood vessel endothelial cell migration / cellular response to vascular endothelial growth factor stimulus / cell fate commitment / vasculogenesis / Integrin cell surface interactions / vascular endothelial growth factor receptor signaling pathway / negative regulation of endothelial cell apoptotic process / coreceptor activity / calcium ion homeostasis / peptidyl-tyrosine autophosphorylation / ovarian follicle development / cell surface receptor protein tyrosine kinase signaling pathway / positive regulation of endothelial cell proliferation / transmembrane receptor protein tyrosine kinase activity / positive regulation of endothelial cell migration / VEGFR2 mediated cell proliferation / stem cell proliferation / epithelial 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 / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / 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 / 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. / Immunoglobulin subtype / Immunoglobulin / Tyrosine-protein kinase, active site / 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-BPK / Vascular endothelial growth factor receptor 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.49 Å
AuthorsIwata, H. / Oki, H. / Okada, K. / Takagi, T. / Tawada, M. / Miyazaki, Y. / Imamura, S. / Hori, A. / Hixon, M.S. / Kimura, H. / Miki, H.
CitationJournal: ACS MED.CHEM.LETT. / Year: 2012
Title: A Back-to-Front Fragment-Based Drug Design Search Strategy Targeting the DFG-Out Pocket of Protein Tyrosine Kinases.
Authors: Iwata, H. / Oki, H. / Okada, K. / Takagi, T. / Tawada, M. / Miyazaki, Y. / Imamura, S. / Hori, A. / Lawson, J.D. / Hixon, M.S. / Kimura, H. / Miki, H.
History
DepositionAug 25, 2011Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Sep 5, 2012Provider: repository / Type: Initial release
Revision 1.1Apr 22, 2015Group: 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 / 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)42,1623
Polymers41,8051
Non-polymers3572
Water75742
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)135.719, 56.354, 51.875
Angle α, β, γ (deg.)90.000, 95.610, 90.000
Int Tables number5
Space group name H-MC121

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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 / Protein-tyrosine kinase ...VEGFR-2 / Fetal liver kinase 1 / FLK-1 / Kinase insert domain receptor / Protein-tyrosine kinase receptor flk-1


Mass: 41804.820 Da / Num. of mol.: 1 / Fragment: UNP RESIDUES 806-1171
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: KDR, FLK1 / Plasmid: pFastBac / Cell line (production host): Sf9 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P35968, receptor protein-tyrosine kinase
#2: Chemical ChemComp-BPK / {3-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]phenyl}methanol


Mass: 295.332 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C18H17NO3
#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.: 42 / 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: 2.36 Å3/Da / Density % sol: 47.91 % / Mosaicity: 0.3 °
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 7
Details: 100mM HEPES, 880-1440mM tri-sodium citrate, pH 7.0-8.0, vapor diffusion, sitting drop, temperature 293K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SPring-8 / Beamline: BL32B2 / Wavelength: 1 Å
DetectorType: RIGAKU JUPITER 210 / Detector: CCD / Date: Oct 11, 2007
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.49→67.57 Å / Num. obs: 13639 / % possible obs: 98.9 % / Redundancy: 3.73 % / Rmerge(I) obs: 0.069 / Χ2: 0.99 / Net I/σ(I): 11.4 / Scaling rejects: 514
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. measured allNum. unique allΧ2Rejects% possible all
2.49-2.583.680.3773.1474212880.86193.7
2.58-2.693.780.3493.3514213590.915100
2.69-2.813.780.2933.9517413690.963100
2.81-2.963.780.2274.5522313800.94799.9
2.96-3.143.770.1795.7509513500.9510100
3.14-3.383.760.127.8519713790.9917100
3.38-3.723.740.08411.6518413781.032599.9
3.72-4.263.740.05418.9522013821.024999.6
4.26-5.373.710.04225.5519113771.088199.7
5.37-37.353.540.03430.5518713771.1431696.5

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Phasing

PhasingMethod: molecular replacement
Phasing MR
Highest resolutionLowest resolution
Rotation3 Å21.63 Å
Translation3 Å21.63 Å

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Processing

Software
NameVersionClassificationNB
d*TREK8.0SSIdata scaling
d*TREK8.0SSIdata reduction
MOLREPphasing
REFMACrefmac_5.2.0019refinement
PDB_EXTRACT3.1data extraction
CrystalCleardata collection
CrystalCleardata reduction
CrystalCleardata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.49→37.35 Å / Cor.coef. Fo:Fc: 0.949 / Cor.coef. Fo:Fc free: 0.916 / WRfactor Rfree: 0.251 / WRfactor Rwork: 0.196 / Occupancy max: 1 / Occupancy min: 1 / SU B: 21.393 / SU ML: 0.23 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R Free: 0.291 / Stereochemistry target values: MAXIMUM LIKELIHOOD
RfactorNum. reflection% reflectionSelection details
Rfree0.2621 681 5 %RANDOM
Rwork0.2068 ---
obs0.2096 13619 98.75 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 90.8 Å2 / Biso mean: 73.172 Å2 / Biso min: 8.44 Å2
Baniso -1Baniso -2Baniso -3
1-1.27 Å20 Å2-0.7 Å2
2---2.14 Å20 Å2
3---0.74 Å2
Refinement stepCycle: LAST / Resolution: 2.49→37.35 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2395 0 26 42 2463
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0060.0222480
X-RAY DIFFRACTIONr_angle_refined_deg0.9231.9753344
X-RAY DIFFRACTIONr_dihedral_angle_1_deg4.9225294
X-RAY DIFFRACTIONr_dihedral_angle_2_deg32.82122.768112
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.89115437
X-RAY DIFFRACTIONr_dihedral_angle_4_deg14.1221520
X-RAY DIFFRACTIONr_chiral_restr0.0610.2357
X-RAY DIFFRACTIONr_gen_planes_refined0.0020.021902
X-RAY DIFFRACTIONr_nbd_refined0.1660.21015
X-RAY DIFFRACTIONr_nbtor_refined0.2980.21680
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.0930.253
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.1360.231
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.1560.23
X-RAY DIFFRACTIONr_mcbond_it1.921531
X-RAY DIFFRACTIONr_mcangle_it3.12332381
X-RAY DIFFRACTIONr_scbond_it4.75941091
X-RAY DIFFRACTIONr_scangle_it6.6776963
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 20

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
2.494-2.5590.3380.247894101991.462
2.559-2.6290.345530.266933986100
2.629-2.7050.378470.278917964100
2.705-2.7880.336460.274852898100
2.788-2.8790.317480.26987892799.892
2.879-2.980.319440.264811855100
2.98-3.0920.368440.25819863100
3.092-3.2180.213430.226761804100
3.218-3.3610.353410.215739780100
3.361-3.5240.261310.206715746100
3.524-3.7150.291370.19367671499.86
3.715-3.9390.215260.19463766699.55
3.939-4.210.245240.18560563099.841
4.21-4.5460.189290.17657660899.507
4.546-4.9780.222330.17449953399.812
4.978-5.5610.267210.17348350599.802
5.561-6.4140.246280.21341344299.774
6.414-7.8380.267220.20735237799.204
7.838-11.0110.138140.14827930097.667
11.011-67.5740.324120.2629917563.429
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)
11.47940.65390.81262.94070.89332.9216-0.0916-0.05540.1007-0.14240.12640.21410.1530.1321-0.03490.09120.03610.01990.0310.01480.0992-33.62526.668.61
22.62080.29940.96632.24530.37791.4570.0635-0.1440.01240.2657-0.0364-0.04450.28830.0986-0.02710.12460.02910.01650.0590.00990.0635-19.11329.45828.487
315.4673-5.9839-4.58375.33165.95787.16310.4148-0.7293-1.59210.7015-0.3633-0.23030.28810.316-0.05150.37580.1301-0.1784-0.02160.30060.3126-11.51512.53236.693
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A814 - 920
2X-RAY DIFFRACTION2A921 - 1107
3X-RAY DIFFRACTION2A1124 - 1168
4X-RAY DIFFRACTION3A1108 - 1123

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