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- PDB-2p2h: Crystal structure of the VEGFR2 kinase domain in complex with a p... -

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Basic information

Entry
Database: PDB / ID: 2p2h
TitleCrystal structure of the VEGFR2 kinase domain in complex with a pyridinyl-triazine inhibitor
ComponentsVascular endothelial growth factor receptor 2VEGF receptor
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 / 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-994 / Vascular endothelial growth factor receptor 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.95 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

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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)36,7152
Polymers36,2851
Non-polymers4301
Water5,098283
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)66.595, 136.915, 58.725
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number18
Space group name H-MP21212

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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.: 1 / Fragment: kinase domain / 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-994 / 4-(2-anilinopyridin-3-yl)-N-(3,4,5-trimethoxyphenyl)-1,3,5-triazin-2-amine


Mass: 430.459 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C23H22N6O3
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 283 / Source method: isolated from a natural source / Formula: H2O

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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: 3.7 Å3/Da / Density % sol: 66.79 %
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

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU / Wavelength: 1.5418 Å
DetectorType: RIGAKU RAXIS IV / Detector: IMAGE PLATE
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 1.95→30 Å / Num. obs: 37501 / % possible obs: 93.8 % / Redundancy: 2.6 % / Rmerge(I) obs: 0.041 / Χ2: 0.982 / Net I/σ(I): 14.9
Reflection shellResolution: 1.95→2.02 Å / Rmerge(I) obs: 0.329 / Mean I/σ(I) obs: 3 / Num. unique all: 3010 / Χ2: 1.504 / % possible all: 76.4

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Phasing

PhasingMethod: molecular replacement
Phasing MRRfactor: 0.41 / Cor.coef. Fo:Fc: 0.594
Highest resolutionLowest resolution
Translation4 Å15 Å

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Processing

Software
NameVersionClassificationNB
SCALEPACKdata scaling
EPMR2.4phasing
CNSrefinement
PDB_EXTRACT1.401data extraction
CrystalClear(MSC/RIGAKU)data collection
DENZOdata reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.95→26.99 Å / Rfactor Rfree error: 0.005 / Data cutoff high absF: 1404753.625 / Data cutoff low absF: 0 / Isotropic thermal model: RESTRAINED / Cross valid method: THROUGHOUT / σ(F): 0 / Stereochemistry target values: Engh & Huber
RfactorNum. reflection% reflectionSelection details
Rfree0.229 1870 5 %RANDOM
Rwork0.205 ---
obs-37484 93.7 %-
Solvent computationSolvent model: FLAT MODEL / Bsol: 33.803 Å2 / ksol: 0.378 e/Å3
Displacement parametersBiso mean: 31.5 Å2
Baniso -1Baniso -2Baniso -3
1--2.99 Å20 Å20 Å2
2--5.37 Å20 Å2
3----2.38 Å2
Refine analyze
FreeObs
Luzzati coordinate error0.27 Å0.23 Å
Luzzati d res low-5 Å
Luzzati sigma a0.21 Å0.2 Å
Refinement stepCycle: LAST / Resolution: 1.95→26.99 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2358 0 32 283 2673
Refine LS restraints
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONc_bond_d0.007
X-RAY DIFFRACTIONc_angle_deg1.22
X-RAY DIFFRACTIONc_dihedral_angle_d21
X-RAY DIFFRACTIONc_improper_angle_d0.742
LS refinement shellResolution: 1.95→2.07 Å / Rfactor Rfree error: 0.019 / Total num. of bins used: 6
RfactorNum. reflection% reflection
Rfree0.318 292 5.3 %
Rwork0.283 5193 -
obs--83.8 %

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