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- PDB-2p2i: Crystal structure of the VEGFR2 kinase domain in complex with a n... -

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Basic information

Entry
Database: PDB / ID: 2p2i
TitleCrystal structure of the VEGFR2 kinase domain in complex with a nicotinamide inhibitor
ComponentsVascular endothelial growth factor receptor 2
KeywordsTRANSFERASE / receptor tyrosine kinase / KDR
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 / 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 ...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 / positive regulation of vasculogenesis / mesenchymal cell proliferation / 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 / embryonic hemopoiesis / positive regulation of endothelial cell chemotaxis / anchoring junction / 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 mitochondrial depolarization / positive regulation of stem cell proliferation / growth factor binding / : / sorting endosome / positive regulation of macroautophagy / semaphorin-plexin signaling pathway / regulation of MAPK cascade / cellular response to vascular endothelial growth factor stimulus / positive regulation of focal adhesion assembly / positive regulation of blood vessel endothelial cell migration / cell fate commitment / Integrin cell surface interactions / vascular endothelial growth factor receptor signaling pathway / vasculogenesis / negative regulation of endothelial cell apoptotic process / peptidyl-tyrosine autophosphorylation / calcium ion homeostasis / coreceptor activity / ovarian follicle development / transmembrane receptor protein tyrosine kinase activity / positive regulation of endothelial cell proliferation / positive regulation of endothelial cell migration / 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 / GPI-linked ephrin receptor activity / transmembrane-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 / 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 / High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells / protein autophosphorylation / angiogenesis / histone H3Y41 kinase activity / histone H2AXY142 kinase activity / negative regulation of neuron apoptotic process / positive regulation of MAPK cascade / positive regulation of ERK1 and ERK2 cascade / positive regulation of protein phosphorylation / early endosome / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / receptor complex / endosome / positive regulation of cell migration / cadherin binding / membrane raft
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. / Immunoglobulin subtype / Immunoglobulin / Tyrosine-protein kinase, active site / Serine-threonine/tyrosine-protein kinase, catalytic domain / Protein tyrosine and serine/threonine kinase / Ig-like domain profile. / Immunoglobulin-like domain / Phosphorylase Kinase; domain 1 / Immunoglobulin-like domain superfamily / Phosphorylase Kinase; domain 1 / Transferase(Phosphotransferase) domain 1 / 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-608 / Vascular endothelial growth factor receptor 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.4 Å
AuthorsWhittington, D.A. / Kim, J.L. / Long, A.M. / Rose, P. / Gu, Y. / Zhao, H.
CitationJournal: J.Med.Chem. / Year: 2007
Title: Evolution of a Highly Selective and Potent 2-(Pyridin-2-yl)-1,3,5-triazine Tie-2 Kinase Inhibitor
Authors: Hodous, B.L. / Geuns-Meyer, S.D. / Hughes, P.E. / Albrecht, B.K. / Bellon, S. / Bready, J. / Caenepeel, S. / Cee, V.J. / Chaffee, S.C. / Coxon, A. / Emery, M. / Fretland, J. / Gallant, P. / ...Authors: Hodous, B.L. / Geuns-Meyer, S.D. / Hughes, P.E. / Albrecht, B.K. / Bellon, S. / Bready, J. / Caenepeel, S. / Cee, V.J. / Chaffee, S.C. / Coxon, A. / Emery, M. / Fretland, J. / Gallant, P. / Gu, Y. / Hoffman, D. / Johnson, R.E. / Kendall, R. / Kim, J.L. / Long, A.M. / Morrison, M. / Olivieri, P.R. / Patel, V.F. / Polverino, A. / Rose, P. / Tempest, P. / Wang, L. / Whittington, D.A. / Zhao, H.
History
DepositionMar 7, 2007Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 20, 2007Provider: repository / Type: Initial release
Revision 1.1May 1, 2008Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Version format compliance
Revision 1.3Aug 16, 2017Group: Refinement description / Source and taxonomy / Category: entity_src_gen / software
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
Revision 1.6Nov 13, 2024Group: Structure summary / Category: pdbx_entry_details

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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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)73,3584
Polymers72,5652
Non-polymers7932
Water2,198122
1
A: Vascular endothelial growth factor receptor 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,6792
Polymers36,2831
Non-polymers3961
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Vascular endothelial growth factor receptor 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,6792
Polymers36,2831
Non-polymers3961
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)55.42, 67.06, 88.51
Angle α, β, γ (deg.)90.00, 94.51, 90.00
Int Tables number4
Space group name H-MP1211

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Components

#1: Protein Vascular endothelial growth factor receptor 2 / VEGFR-2 / Kinase insert domain receptor / Protein-tyrosine kinase receptor Flk-1 / CD309 antigen


Mass: 36282.613 Da / Num. of mol.: 2 / Fragment: kinase domain / Mutation: C817A, 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-608 / N-(4-phenoxyphenyl)-2-[(pyridin-4-ylmethyl)amino]nicotinamide


Mass: 396.441 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C24H20N4O2
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 122 / Source method: isolated from a natural source / Formula: H2O
Has protein modificationN

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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: 2.27 Å3/Da / Density % sol: 45.78 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 8
Details: pH 8.0, VAPOR DIFFUSION, HANGING DROP, temperature 277K

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Data collection

Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.2
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthRelative weight: 1
ReflectionResolution: 2.4→40 Å / Num. obs: 23837 / % possible obs: 94.1 % / Redundancy: 2.5 % / Rmerge(I) obs: 0.098 / Χ2: 1.248 / Net I/σ(I): 9.6
Reflection shellResolution: 2.4→2.49 Å / Rmerge(I) obs: 0.415 / Mean I/σ(I) obs: 2 / Num. unique all: 2186 / Χ2: 1.01 / % possible all: 87.6

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Phasing

PhasingMethod: molecular replacement
Phasing MRRfactor: 0.565 / Cor.coef. Fo:Fc: 0.219
Highest resolutionLowest resolution
Translation3.5 Å20 Å

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Processing

Software
NameVersionClassificationNB
SCALEPACKdata scaling
EPMR2.4phasing
CNSrefinement
PDB_EXTRACT1.401data extraction
DENZOdata reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.4→36.86 Å / Rfactor Rfree error: 0.008 / Data cutoff high absF: 1700177.875 / Data cutoff low absF: 0 / Isotropic thermal model: RESTRAINED / Cross valid method: THROUGHOUT / σ(F): 0
RfactorNum. reflection% reflectionSelection details
Rfree0.266 1128 4.8 %RANDOM
Rwork0.222 ---
obs-23375 91.8 %-
Solvent computationSolvent model: FLAT MODEL / Bsol: 30.461 Å2 / ksol: 0.349 e/Å3
Displacement parametersBiso mean: 32 Å2
Baniso -1Baniso -2Baniso -3
1--8.69 Å20 Å20.11 Å2
2---3.25 Å20 Å2
3---11.94 Å2
Refine analyze
FreeObs
Luzzati coordinate error0.38 Å0.32 Å
Luzzati d res low-5 Å
Luzzati sigma a0.46 Å0.56 Å
Refinement stepCycle: LAST / Resolution: 2.4→36.86 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4341 0 60 122 4523
Refine LS restraints
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONc_bond_d0.009
X-RAY DIFFRACTIONc_angle_deg1.39
X-RAY DIFFRACTIONc_dihedral_angle_d22.5
X-RAY DIFFRACTIONc_improper_angle_d0.821
LS refinement shellResolution: 2.4→2.55 Å / Rfactor Rfree error: 0.026 / Total num. of bins used: 6
RfactorNum. reflection% reflection
Rfree0.323 149 4.4 %
Rwork0.335 3247 -
obs--81.3 %

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