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- PDB-3cp9: Crystal structure of the VEGFR2 kinase domain in complex with a p... -

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Basic information

Entry
Database: PDB / ID: 3cp9
TitleCrystal structure of the VEGFR2 kinase domain in complex with a pyridone inhibitor
ComponentsVascular endothelial growth factor receptor 2VEGF receptor
KeywordsTRANSFERASE / receptor tyrosine kinase / angiogenesis / ATP-binding / Developmental protein / Differentiation / Glycoprotein / Host-virus interaction / Immunoglobulin domain / Membrane / Nucleotide-binding / Phosphoprotein / Polymorphism / Transmembrane / Tyrosine-protein kinase
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 / regulation of hematopoietic progenitor cell differentiation / endothelium development / Neurophilin interactions with VEGF and VEGFR / vascular endothelial growth factor binding / positive regulation of endothelial cell chemotaxis by VEGF-activated vascular endothelial growth factor receptor signaling pathway / vascular endothelial growth factor receptor-2 signaling pathway ...blood vessel endothelial cell differentiation / cellular response to hydrogen sulfide / regulation of bone development / Signaling by membrane-tethered fusions of PDGFRA or PDGFRB / regulation of hematopoietic progenitor cell differentiation / endothelium development / Neurophilin interactions with VEGF and VEGFR / vascular endothelial growth factor binding / positive regulation of endothelial cell chemotaxis by VEGF-activated vascular endothelial growth factor receptor signaling pathway / 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 / 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 / epithelial cell maturation / anchoring junction / cell migration involved in sprouting angiogenesis / positive regulation of positive chemotaxis / vascular endothelial growth factor signaling pathway / embryonic hemopoiesis / positive regulation of mesenchymal cell proliferation / positive regulation of mitochondrial fission / positive regulation of mitochondrial depolarization / branching involved in blood vessel morphogenesis / positive regulation of cell migration involved in sprouting angiogenesis / lung alveolus development / positive regulation of stem cell proliferation / positive regulation of nitric-oxide synthase biosynthetic process / growth factor binding / sorting endosome / positive regulation of focal adhesion assembly / regulation of MAPK cascade / positive regulation of macroautophagy / semaphorin-plexin signaling pathway / : / positive regulation of blood vessel endothelial cell migration / cellular response to vascular endothelial growth factor stimulus / calcium ion homeostasis / cell fate commitment / vasculogenesis / Integrin cell surface interactions / 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 / Hsp90 protein binding / receptor protein-tyrosine kinase / VEGFA-VEGFR2 Pathway / peptidyl-tyrosine phosphorylation / cell surface receptor protein tyrosine kinase signaling pathway / 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 ERK1 and ERK2 cascade / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / receptor complex / early endosome / 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 / 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-C19 / Vascular endothelial growth factor receptor 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 2.5 Å
AuthorsWhittington, D.A. / Long, A.M. / Rose, P. / Gu, Y. / Zhao, H.
CitationJournal: J.Med.Chem. / Year: 2008
Title: Discovery of Aryl Aminoquinazoline Pyridones as Potent, Selective, and Orally Efficacious Inhibitors of Receptor Tyrosine Kinase c-Kit.
Authors: Hu, E. / Tasker, A. / White, R.D. / Kunz, R.K. / Human, J. / Chen, N. / Burli, R. / Hungate, R. / Novak, P. / Itano, A. / Zhang, X. / Yu, V. / Nguyen, Y. / Tudor, Y. / Plant, M. / Flynn, S. ...Authors: Hu, E. / Tasker, A. / White, R.D. / Kunz, R.K. / Human, J. / Chen, N. / Burli, R. / Hungate, R. / Novak, P. / Itano, A. / Zhang, X. / Yu, V. / Nguyen, Y. / Tudor, Y. / Plant, M. / Flynn, S. / Xu, Y. / Meagher, K.L. / Whittington, D.A. / Ng, G.Y.
History
DepositionMar 31, 2008Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 17, 2008Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Jul 26, 2017Group: Source and taxonomy / Category: entity_src_gen
Revision 1.3Jun 13, 2018Group: Data collection / Database references / Source and taxonomy
Category: entity_src_gen / struct_ref ...entity_src_gen / struct_ref / struct_ref_seq / struct_ref_seq_dif
Item: _entity_src_gen.pdbx_gene_src_ncbi_taxonomy_id / _entity_src_gen.pdbx_host_org_ncbi_taxonomy_id
Revision 1.4Oct 20, 2021Group: Database references / Derived calculations / Category: 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
Revision 1.5Feb 21, 2024Group: Data collection / Category: chem_comp_atom / chem_comp_bond

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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
B: Vascular endothelial growth factor receptor 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)73,3644
Polymers72,5692
Non-polymers7952
Water2,126118
1
A: Vascular endothelial growth factor receptor 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,6822
Polymers36,2851
Non-polymers3971
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Vascular endothelial growth factor receptor 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,6822
Polymers36,2851
Non-polymers3971
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)55.570, 67.170, 89.102
Angle α, β, γ (deg.)90.00, 93.076, 90.00
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 / Kinase insert domain receptor / Protein-tyrosine kinase receptor Flk-1 / CD309 antigen


Mass: 36284.586 Da / Num. of mol.: 2 / Fragment: PROTEIN KINASE DOMAIN, RESIDUES 940-989 DELETED / Mutation: C817A, V916T, E990V, delete(940-989)
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: KDR, FLK1 / Production host: Trichoplusia ni (cabbage looper)
References: UniProt: P35968, receptor protein-tyrosine kinase
#2: Chemical ChemComp-C19 / 3-(2-aminoquinazolin-6-yl)-1-(3,3-dimethylindolin-6-yl)-4-methylpyridin-2(1H)-one


Mass: 397.472 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C24H23N5O
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 118 / Source method: isolated from a natural source / Formula: H2O
Nonpolymer detailsTYR1054 AND TYR1059 WERE PHOSPHORYLATED BY AN AUTOPHOSPHORYLATION REACTION RUN ON THE PROTEIN PRIOR ...TYR1054 AND TYR1059 WERE PHOSPHORYLATED BY AN AUTOPHOSPHORYLATION REACTION RUN ON THE PROTEIN PRIOR TO CRYSTALLIZATION. THE PHOSPHORYLATED TYR IS REPRESENTED BY PTR, PHOSPHONOTYROSINE, PTR1054 AND PTR1059. THESE RESIDUES ARE PART OF THE KINASE ACTIVATION LOOP AND THEY ARE DISORDERED IN THE STRUCTURE AND CONSEQUENTLY NOT SEEN IN THE ELECTRON DENSITY.

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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: 2.29 Å3/Da / Density % sol: 46.25 %
Crystal growTemperature: 277 K / Method: vapor diffusion / pH: 8
Details: PEG 5000 MME, HEPES, ammonium sulfate, sodium chloride, isopropanol, beta-mercaptoethanol , pH 8.0, VAPOR DIFFUSION, temperature 277K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 31-ID / Wavelength: 0.9793 Å
DetectorType: MAR CCD 165 mm / Detector: CCD
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9793 Å / Relative weight: 1
ReflectionResolution: 2.5→30 Å / Num. all: 22869 / Num. obs: 22862 / % possible obs: 100 % / Observed criterion σ(I): -3 / Redundancy: 4.1 % / Biso Wilson estimate: 42.8 Å2 / Rmerge(I) obs: 0.093 / Χ2: 1.083 / Net I/σ(I): 15
Reflection shellResolution: 2.5→2.59 Å / Redundancy: 4.1 % / Rmerge(I) obs: 0.494 / Mean I/σ(I) obs: 3.1 / Num. unique all: 2249 / Χ2: 1.075 / % possible all: 100

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Processing

Software
NameVersionClassificationNB
SCALEPACKdata scaling
CNSrefinement
PDB_EXTRACT1.401data extraction
DENZOdata reduction
CNSphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 2.5→30 Å / Data cutoff high absF: 10000 / Data cutoff low absF: 0 / Cross valid method: THROUGHOUT / σ(F): 0
RfactorNum. reflection% reflectionSelection details
Rfree0.263 1341 5.9 %random
Rwork0.211 ---
all-22857 --
obs-22848 100 %-
Displacement parameters
Baniso -1Baniso -2Baniso -3
1-4.569 Å20 Å2-3.871 Å2
2--4.238 Å20 Å2
3----8.807 Å2
Refine analyze
FreeObs
Luzzati coordinate error0.4 Å0.3 Å
Luzzati d res low-5 Å
Luzzati sigma a0.37 Å0.29 Å
Refinement stepCycle: LAST / Resolution: 2.5→30 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4491 0 60 118 4669
Refine LS restraints
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONc_angle_deg1.27
X-RAY DIFFRACTIONc_bond_d0.007
X-RAY DIFFRACTIONc_dihedral_angle_d21.3
X-RAY DIFFRACTIONc_improper_angle_d0.76

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