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- PDB-6xvj: Crystal structure of the KDR (VEGFR2) kinase domain in complex wi... -

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Basic information

Entry
Database: PDB / ID: 6xvj
TitleCrystal structure of the KDR (VEGFR2) kinase domain in complex with a type-II inhibitor
ComponentsVascular endothelial growth factor receptor 2VEGF receptor
KeywordsSIGNALING PROTEIN / type II kinase inhibitor / structure-based drug design
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 / 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
Similarity search - Domain/homology
Chem-O35 / Vascular endothelial growth factor receptor 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.78 Å
AuthorsSchimpl, M. / McAuley, K. / Hoyt, E.A. / Thomas, M. / Bodnarchuk, M.S. / Lewis, H.J. / Barratt, D. / Deery, M.J. / Ogg, D.J. / Bernardes, G.J.L. ...Schimpl, M. / McAuley, K. / Hoyt, E.A. / Thomas, M. / Bodnarchuk, M.S. / Lewis, H.J. / Barratt, D. / Deery, M.J. / Ogg, D.J. / Bernardes, G.J.L. / Ward, R.A. / Kettle, J.G. / Waring, M.J.
CitationJournal: J.Am.Chem.Soc. / Year: 2020
Title: Alkynyl Benzoxazines and Dihydroquinazolines as Cysteine Targeting Covalent Warheads and Their Application in Identification of Selective Irreversible Kinase Inhibitors.
Authors: McAulay, K. / Hoyt, E.A. / Thomas, M. / Schimpl, M. / Bodnarchuk, M.S. / Lewis, H.J. / Barratt, D. / Bhavsar, D. / Robinson, D.M. / Deery, M.J. / Ogg, D.J. / Bernardes, G.J.L. / Ward, R.A. / ...Authors: McAulay, K. / Hoyt, E.A. / Thomas, M. / Schimpl, M. / Bodnarchuk, M.S. / Lewis, H.J. / Barratt, D. / Bhavsar, D. / Robinson, D.M. / Deery, M.J. / Ogg, D.J. / Bernardes, G.J.L. / Ward, R.A. / Waring, M.J. / Kettle, J.G.
History
DepositionJan 22, 2020Deposition site: PDBE / Processing site: PDBE
Revision 1.0May 27, 2020Provider: repository / Type: Initial release
Revision 1.1Jun 17, 2020Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.name
Revision 1.2May 1, 2024Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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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)37,4762
Polymers36,9901
Non-polymers4871
Water3,693205
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area15180 Å2
MethodPISA
Unit cell
Length a, b, c (Å)51.724, 56.257, 60.260
Angle α, β, γ (deg.)90.000, 110.400, 90.000
Int Tables number4
Space group name H-MP1211

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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


Mass: 36989.609 Da / Num. of mol.: 1 / Fragment: protein kinase domain (807-1171 del[940-989]) / Mutation: E990V
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: KDR, FLK1, VEGFR2 / Plasmid: pFastBac1 / Cell line (production host): Sf21 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P35968, receptor protein-tyrosine kinase
#2: Chemical ChemComp-O35 / ~{N}-[3-[(dimethylamino)methyl]-5-methyl-phenyl]-2-[3-methoxy-5-(7-methoxyquinolin-4-yl)oxy-pyridin-2-yl]ethanamide


Mass: 486.562 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C28H30N4O4 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 205 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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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: 2.22 Å3/Da / Density % sol: 44.63 % / Mosaicity: 0.42 °
Crystal growTemperature: 293 K / Method: vapor diffusion / pH: 8.5
Details: 25 % PEG550MME, 0.1 M NaCl, 0.1 M TRIS buffer pH 8.5

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I03 / Wavelength: 0.97626 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Aug 1, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97626 Å / Relative weight: 1
ReflectionResolution: 1.78→56.48 Å / Num. obs: 29228 / % possible obs: 93.5 % / Redundancy: 3.2 % / Biso Wilson estimate: 30.67 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.042 / Rpim(I) all: 0.027 / Rrim(I) all: 0.05 / Net I/σ(I): 15.4 / Num. measured all: 93735
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. measured allNum. unique obsCC1/2Rpim(I) allRrim(I) allNet I/σ(I) obs% possible all
1.78-1.883.30.491477845330.8010.3190.5872.399.9
5.63-56.483.10.025323510330.9980.0170.033999.2

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassificationNB
XDSdata reduction
Aimless0.5.12data scaling
AMoREphasing
BUSTERrefinement
PDB_EXTRACT3.25data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: internal model

Resolution: 1.78→48.48 Å / Cor.coef. Fo:Fc: 0.955 / Cor.coef. Fo:Fc free: 0.95 / SU R Cruickshank DPI: 0.123 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.126 / SU Rfree Blow DPI: 0.119 / SU Rfree Cruickshank DPI: 0.118
RfactorNum. reflection% reflectionSelection details
Rfree0.215 1415 4.84 %RANDOM
Rwork0.178 ---
obs0.18 29206 93.5 %-
Displacement parametersBiso max: 119.43 Å2 / Biso mean: 36.22 Å2 / Biso min: 16.46 Å2
Baniso -1Baniso -2Baniso -3
1-3.8222 Å20 Å2-0.1467 Å2
2---0.086 Å20 Å2
3----3.7362 Å2
Refine analyzeLuzzati coordinate error obs: 0.22 Å
Refinement stepCycle: final / Resolution: 1.78→48.48 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2443 0 36 205 2684
Biso mean--24.57 43.17 -
Num. residues----305
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d888SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes422HARMONIC5
X-RAY DIFFRACTIONt_it2543HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion314SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact3133SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d2543HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg3440HARMONIC20.99
X-RAY DIFFRACTIONt_omega_torsion3.48
X-RAY DIFFRACTIONt_other_torsion17.73
LS refinement shellResolution: 1.78→1.79 Å / Rfactor Rfree error: 0 / Total num. of bins used: 50
RfactorNum. reflection% reflection
Rfree0.3372 27 4.62 %
Rwork0.2086 558 -
all0.2143 585 -
obs--99.47 %
Refinement TLS params.Method: refined / Origin x: 21.3629 Å / Origin y: -0.5065 Å / Origin z: 12.1668 Å
111213212223313233
T-0.0805 Å20.0003 Å20.0163 Å2--0.0564 Å2-0.0068 Å2---0.0858 Å2
L1.2963 °2-0.1197 °20.1831 °2-1.044 °2-0.334 °2--1.182 °2
S-0.0131 Å °-0.165 Å °-0.0181 Å °0.1304 Å °-0.0203 Å °-0.0104 Å °-0.0523 Å °0.1959 Å °0.0334 Å °
Refinement TLS groupSelection details: { A|* }

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