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- PDB-4agd: CRYSTAL STRUCTURE OF VEGFR2 (JUXTAMEMBRANE AND KINASE DOMAINS) IN... -

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Basic information

Entry
Database: PDB / ID: 4agd
TitleCRYSTAL STRUCTURE OF VEGFR2 (JUXTAMEMBRANE AND KINASE DOMAINS) IN COMPLEX WITH SUNITINIB (SU11248) (N-2-diethylaminoethyl)-5-((Z)-(5- fluoro-2-oxo-1H-indol-3-ylidene)methyl)-2,4-dimethyl-1H-pyrrole-3- carboxamide)
ComponentsVASCULAR ENDOTHELIAL GROWTH FACTOR RECEPTOR 2VEGF receptor
KeywordsTRANSFERASE / ANGIOGENESIS / NUCLEOTIDE-BINDING / INHIBITOR / PHOSPHORYLATION / TRANSMEMBRANE
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-B49 / Vascular endothelial growth factor receptor 2
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.81 Å
AuthorsMcTigue, M. / Deng, Y. / Ryan, K. / Brooun, A. / Diehl, W. / Stewart, A.
CitationJournal: Proc.Natl.Acad.Sci.USA / Year: 2012
Title: Molecular Conformations, Interactions, and Properties Associated with Drug Efficiency and Clinical Performance Among Vegfr Tk Inhibitors.
Authors: Mctigue, M. / Murray, B.W. / Chen, J.H. / Deng, Y. / Solowiej, J. / Kania, R.S.
History
DepositionJan 26, 2012Deposition site: PDBE / Processing site: PDBE
Revision 1.0Sep 26, 2012Provider: repository / Type: Initial release
Revision 1.1Nov 14, 2012Group: Database references
Revision 1.2May 8, 2019Group: Data collection / Experimental preparation / Other
Category: database_PDB_rev / database_PDB_rev_record ...database_PDB_rev / database_PDB_rev_record / exptl_crystal_grow / pdbx_database_proc / pdbx_database_status
Item: _exptl_crystal_grow.method / _exptl_crystal_grow.temp / _pdbx_database_status.recvd_author_approval
Revision 1.3Dec 20, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Other / Refinement description / Structure summary
Category: chem_comp / chem_comp_atom ...chem_comp / chem_comp_atom / chem_comp_bond / database_2 / entity / pdbx_database_status / pdbx_entity_nonpoly / pdbx_initial_refinement_model / struct_site
Item: _chem_comp.name / _database_2.pdbx_DOI ..._chem_comp.name / _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _entity.pdbx_description / _pdbx_database_status.status_code_sf / _pdbx_entity_nonpoly.name / _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

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Assembly

Deposited unit
A: VASCULAR ENDOTHELIAL GROWTH FACTOR RECEPTOR 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)40,6572
Polymers40,2581
Non-polymers3981
Water1,56787
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)134.694, 56.980, 52.720
Angle α, β, γ (deg.)90.00, 94.34, 90.00
Int Tables number5
Space group name H-MC121

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Components

#1: Protein VASCULAR ENDOTHELIAL GROWTH FACTOR RECEPTOR 2 / VEGF receptor / 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 / CD309


Mass: 40258.391 Da / Num. of mol.: 1
Fragment: JUXTAMEMBRANE AND KINASE DOMAINS, RESIDUES 787-939,990-1171
Mutation: YES
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Plasmid: PFASTBAC / Cell line (production host): SF9 / Production host: SPODOPTERA FRUGIPERDA (fall armyworm)
References: UniProt: P35968, receptor protein-tyrosine kinase
#2: Chemical ChemComp-B49 / N-[2-(diethylamino)ethyl]-5-[(Z)-(5-fluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-carbo xamide / SUNITINIB / Sunitinib


Mass: 398.474 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C22H27FN4O2 / Comment: medication, anticancer, inhibitor*YM
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 87 / Source method: isolated from a natural source / Formula: H2O
Compound detailsENGINEERED RESIDUE IN CHAIN A, GLU 990 TO VAL

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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: 2.6 Å3/Da / Density % sol: 53.2 % / Description: NONE
Crystal growTemperature: 286 K / Method: vapor diffusion, hanging drop / pH: 6.2
Details: CRYSTALS WERE GROWN AT 13 DEGREES C BY THE HANGING DROP VAPOR DIFFUSION METHOD USING PRECIPITANT SOLUTIONS CONTAINING: 0.222 M SODIUM CITRATE (PH 6.3) AND 17% (W/V) POLYETHYLENE GLYCOL 3350

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Data collection

DiffractionMean temperature: 87 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 21-ID-D / Wavelength: 1
DetectorType: MARRESEARCH / Detector: IMAGE PLATE / Date: Dec 1, 2008
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.8→40 Å / Num. obs: 9095 / % possible obs: 92.4 % / Observed criterion σ(I): 2 / Redundancy: 3.4 % / Biso Wilson estimate: 26.5 Å2 / Rmerge(I) obs: 0.06 / Net I/σ(I): 19.5
Reflection shellResolution: 2.8→2.9 Å / Redundancy: 2.2 % / Rmerge(I) obs: 0.23 / Mean I/σ(I) obs: 2.2 / % possible all: 55.7

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Processing

Software
NameVersionClassification
CNS2005refinement
HKL-2000data reduction
SCALEPACKdata scaling
CCP4phasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 4AGC

4agc


Resolution: 2.81→37.69 Å / Rfactor Rfree error: 0.018 / Data cutoff high absF: 64241.02 / Data cutoff low absF: 0 / Isotropic thermal model: RESTRAINED / Cross valid method: THROUGHOUT / σ(F): 0
RfactorNum. reflection% reflectionSelection details
Rfree0.307 282 3.2 %RANDOM
Rwork0.21 ---
obs0.21 8793 88.2 %-
Solvent computationSolvent model: FLAT MODEL / Bsol: 54.0271 Å2 / ksol: 0.33577 e/Å3
Displacement parametersBiso mean: 66.3 Å2
Baniso -1Baniso -2Baniso -3
1--11.96 Å20 Å2-8.38 Å2
2---3.31 Å20 Å2
3---15.28 Å2
Refine analyze
FreeObs
Luzzati coordinate error0.49 Å0.34 Å
Luzzati d res low-5 Å
Luzzati sigma a0.39 Å0.4 Å
Refinement stepCycle: LAST / Resolution: 2.81→37.69 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2430 0 29 87 2546
Refine LS restraints
Refine-IDTypeDev idealDev ideal target
X-RAY DIFFRACTIONc_bond_d0.007
X-RAY DIFFRACTIONc_bond_d_na
X-RAY DIFFRACTIONc_bond_d_prot
X-RAY DIFFRACTIONc_angle_d
X-RAY DIFFRACTIONc_angle_d_na
X-RAY DIFFRACTIONc_angle_d_prot
X-RAY DIFFRACTIONc_angle_deg1
X-RAY DIFFRACTIONc_angle_deg_na
X-RAY DIFFRACTIONc_angle_deg_prot
X-RAY DIFFRACTIONc_dihedral_angle_d22.2
X-RAY DIFFRACTIONc_dihedral_angle_d_na
X-RAY DIFFRACTIONc_dihedral_angle_d_prot
X-RAY DIFFRACTIONc_improper_angle_d0.71
X-RAY DIFFRACTIONc_improper_angle_d_na
X-RAY DIFFRACTIONc_improper_angle_d_prot
X-RAY DIFFRACTIONc_mcbond_it1.521.5
X-RAY DIFFRACTIONc_mcangle_it2.722
X-RAY DIFFRACTIONc_scbond_it1.792
X-RAY DIFFRACTIONc_scangle_it2.932.5
Refine LS restraints NCSNCS model details: NONE
LS refinement shellResolution: 2.8→2.98 Å / Rfactor Rfree error: 0.064 / Total num. of bins used: 6
RfactorNum. reflection% reflection
Rfree0.325 26 3.1 %
Rwork0.299 805 -
obs--51 %
Xplor file
Refine-IDSerial noParam fileTopol file
X-RAY DIFFRACTION1PROTEIN_REP.PARAMPROTEIN.TOP
X-RAY DIFFRACTION2DNA-RNA_REP.PARAMDNA-RNA.TOP
X-RAY DIFFRACTION3WATER_REP.PARAMWATER.TOP
X-RAY DIFFRACTION4ION.PARAMION.TOP
X-RAY DIFFRACTION5MOL.PARAMMOL.TOP

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