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- PDB-4asd: Crystal Structure of VEGFR2 (Juxtamembrane and Kinase Domains) in... -

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Entry
Database: PDB / ID: 4asd
TitleCrystal Structure of VEGFR2 (Juxtamembrane and Kinase Domains) in Complex with SORAFENIB (BAY 43-9006)
ComponentsVASCULAR ENDOTHELIAL GROWTH FACTOR RECEPTOR 2
KeywordsTRANSFERASE / ANGIOGENESIS / NUCLEOTIDE-BINDING / INHIBITOR / PHOSPHORYLATION / RECEPTOR / KDR
Function / homology
Function and homology information


positive regulation of nitric oxide-cGMP mediated signal transduction / blood vessel endothelial cell differentiation / cellular response to hydrogen sulfide / regulation of bone development / 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 / cellular response to hydrogen sulfide / regulation of bone development / 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 / regulation of hematopoietic progenitor cell differentiation / post-embryonic camera-type eye morphogenesis / lymph vessel development / mesenchymal cell proliferation / positive regulation of vasculogenesis / endothelial cell differentiation / 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 / anchoring junction / embryonic hemopoiesis / vascular endothelial growth factor signaling pathway / positive regulation of mesenchymal cell proliferation / positive regulation of cell migration involved in sprouting angiogenesis / positive regulation of mitochondrial fission / branching involved in blood vessel morphogenesis / lung alveolus development / positive regulation of stem cell proliferation / positive regulation of mitochondrial depolarization / growth factor binding / sorting endosome / regulation of MAPK cascade / semaphorin-plexin signaling pathway / positive regulation of macroautophagy / cellular response to vascular endothelial growth factor stimulus / positive regulation of focal adhesion assembly / cell fate commitment / positive regulation of blood vessel endothelial cell migration / Integrin cell surface interactions / vascular endothelial growth factor receptor signaling pathway / negative regulation of endothelial cell apoptotic process / vasculogenesis / peptidyl-tyrosine autophosphorylation / calcium ion homeostasis / coreceptor activity / ovarian follicle development / 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 / VEGFR2 mediated cell proliferation / epithelial cell proliferation / stem cell proliferation / Hsp90 protein binding / placental growth factor receptor activity / insulin receptor activity / vascular endothelial growth factor receptor activity / hepatocyte growth factor receptor activity / macrophage colony-stimulating factor receptor activity / platelet-derived growth factor alpha-receptor activity / platelet-derived growth factor beta-receptor activity / stem cell factor receptor activity / boss receptor activity / protein tyrosine kinase collagen receptor activity / brain-derived neurotrophic factor receptor activity / transmembrane-ephrin receptor activity / GPI-linked ephrin receptor activity / epidermal growth factor receptor activity / fibroblast growth factor receptor activity / insulin-like growth factor receptor activity / receptor protein-tyrosine kinase / peptidyl-tyrosine phosphorylation / VEGFA-VEGFR2 Pathway / positive regulation of angiogenesis / integrin binding / cell junction / cell migration / regulation of cell shape / positive regulation of protein phosphorylation / protein autophosphorylation / High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells / protein tyrosine kinase activity / angiogenesis / negative regulation of neuron apoptotic process / early endosome / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / receptor complex / positive regulation of ERK1 and ERK2 cascade / positive regulation of MAPK cascade / endosome / positive regulation of cell migration / cadherin binding / membrane raft / external side of plasma membrane / negative regulation of gene expression
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. / Tyrosine-protein kinase, active site / Immunoglobulin subtype / Immunoglobulin / Serine-threonine/tyrosine-protein kinase, catalytic domain / Protein tyrosine and serine/threonine kinase / Phosphorylase Kinase; domain 1 / Ig-like domain profile. / Immunoglobulin-like domain / Phosphorylase Kinase; domain 1 / Transferase(Phosphotransferase) domain 1 / Immunoglobulin-like domain superfamily / Transferase(Phosphotransferase); domain 1 / 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-BAX / Vascular endothelial growth factor receptor 2
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.03 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
DepositionApr 30, 2012Deposition site: PDBE / Processing site: PDBE
Revision 1.0Sep 26, 2012Provider: repository / Type: Initial release
Revision 1.1Oct 3, 2012Group: Non-polymer description
Revision 1.2Nov 14, 2012Group: Database references
Revision 1.3May 23, 2018Group: Data collection / Database references / Structure summary
Category: citation_author / struct / Item: _citation_author.name / _struct.title
Revision 1.4May 8, 2019Group: Data collection / Experimental preparation
Category: database_PDB_rev / database_PDB_rev_record / exptl_crystal_grow
Item: _exptl_crystal_grow.method / _exptl_crystal_grow.temp
Revision 1.5Dec 20, 2023Group: Data collection / Database references ...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 / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _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)40,7232
Polymers40,2581
Non-polymers4651
Water6,359353
1


  • Idetical with deposited unit
  • defined by software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)135.818, 56.479, 52.052
Angle α, β, γ (deg.)90.00, 95.42, 90.00
Int Tables number5
Space group name H-MC121

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Components

#1: Protein VASCULAR ENDOTHELIAL GROWTH FACTOR RECEPTOR 2 / VEGFR-2 / 2.7.10.1 / FETAL LIVER KINASE 1 / FLK-1 / KINASE INSERT DOMAIN RECEPTOR / KDR / PROTEIN- ...VEGFR-2 / 2.7.10.1 / 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 AND RESIDUES 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-BAX / 4-{4-[({[4-CHLORO-3-(TRIFLUOROMETHYL)PHENYL]AMINO}CARBONYL)AMINO]PHENOXY}-N-METHYLPYRIDINE-2-CARBOXAMIDE / Sorafenib


Mass: 464.825 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H16ClF3N4O3 / Comment: inhibitor*YM
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 353 / Source method: isolated from a natural source / Formula: H2O
Compound detailsENGINEERED RESIDUE IN CHAIN A, GLU 990 TO VAL
Sequence detailsRESIDUES 940-989 OF THE KINASE INSERT DOMAIN ARE DELETED. THERE IS ONE POINT MUTATION (E990V).

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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 % / Description: NONE
Crystal growTemperature: 286 K / Method: vapor diffusion, hanging drop / pH: 6.2
Details: CRYSTALS WERE OBTAINED BY THE HANGING DROP VAPOR DIFFUSION METHOD AT 13 DEGREES C USING PRECIPITANT SOLUTIONS CONTAINING APPROXIMATELY: 0.2M SODIUM CITRATE AND 14-21% (W/V) POLYETHYLENE GLYCOL 3350., pH 6.2

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Data collection

DiffractionMean temperature: 81 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU RU2000 / Wavelength: 1.5418
DetectorType: MARRESEARCH / Detector: IMAGE PLATE / Date: Dec 5, 2007 / Details: MIRRORS
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2.02→50 Å / Num. obs: 23908 / % possible obs: 92.2 % / Observed criterion σ(I): 1 / Redundancy: 3.7 % / Rmerge(I) obs: 0.04 / Net I/σ(I): 38
Reflection shellResolution: 2.02→2.09 Å / Redundancy: 1.9 % / Rmerge(I) obs: 0.13 / Mean I/σ(I) obs: 6 / % possible all: 43.6

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Processing

Software
NameVersionClassification
REFMAC5.2.0019refinement
HKL-2000data reduction
SCALEPACKdata scaling
CCP4phasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 4AG8

4ag8


Resolution: 2.03→15 Å / Cor.coef. Fo:Fc: 0.956 / Cor.coef. Fo:Fc free: 0.927 / SU B: 3.689 / SU ML: 0.104 / Cross valid method: THROUGHOUT / ESU R: 0.187 / ESU R Free: 0.173 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS.
RfactorNum. reflection% reflectionSelection details
Rfree0.23022 1218 5.1 %RANDOM
Rwork0.17547 ---
obs0.17831 22631 94 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 29.658 Å2
Baniso -1Baniso -2Baniso -3
1-0.84 Å20 Å2-0.37 Å2
2---0.44 Å20 Å2
3----0.47 Å2
Refinement stepCycle: LAST / Resolution: 2.03→15 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2453 0 32 353 2838
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0120.0222561
X-RAY DIFFRACTIONr_bond_other_d0.0030.028
X-RAY DIFFRACTIONr_angle_refined_deg1.3031.9833463
X-RAY DIFFRACTIONr_angle_other_deg0.694314
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.7475305
X-RAY DIFFRACTIONr_dihedral_angle_2_deg32.99923.017116
X-RAY DIFFRACTIONr_dihedral_angle_3_deg17.19215445
X-RAY DIFFRACTIONr_dihedral_angle_4_deg21.0021520
X-RAY DIFFRACTIONr_chiral_restr0.1010.2369
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.021954
X-RAY DIFFRACTIONr_gen_planes_other0.0020.027
X-RAY DIFFRACTIONr_nbd_refined0.1950.21215
X-RAY DIFFRACTIONr_nbd_other0.3750.210
X-RAY DIFFRACTIONr_nbtor_refined0.3070.21732
X-RAY DIFFRACTIONr_nbtor_other0.2250.210
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.2380.2280
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.2490.256
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.1850.222
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it0.7991.51580
X-RAY DIFFRACTIONr_mcbond_other0.1611.53
X-RAY DIFFRACTIONr_mcangle_it1.36522466
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it2.00331131
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it3.1024.5997
X-RAY DIFFRACTIONr_scangle_other
X-RAY DIFFRACTIONr_long_range_B_refined
X-RAY DIFFRACTIONr_long_range_B_other
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.033→2.085 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.263 37 -
Rwork0.213 892 -
obs--50.13 %

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