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- PDB-3vhe: Crystal structure of human VEGFR2 kinase domain with a novel pyrr... -

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Basic information

Entry
Database: PDB / ID: 3vhe
TitleCrystal structure of human VEGFR2 kinase domain with a novel pyrrolopyrimidine inhibitor.
ComponentsVascular endothelial growth factor receptor 2
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / KINASE DOMAIN / KINASE / TRANSFERASE-TRANSFERASE INHIBITOR complex
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-42Q / Vascular endothelial growth factor receptor 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.55 Å
AuthorsOguro, Y. / Miyamoto, N. / Okada, K. / Takagi, T. / Iwata, H. / Awazu, Y. / Miki, H. / Hori, A. / Kamiyama, K. / Imanura, S.
CitationJournal: Bioorg.Med.Chem. / Year: 2010
Title: Design, synthesis, and evaluation of 5-methyl-4-phenoxy-5H-pyrrolo[3,2-d]pyrimidine derivatives: novel VEGFR2 kinase inhibitors binding to inactive kinase conformation.
Authors: Oguro, Y. / Miyamoto, N. / Okada, K. / Takagi, T. / Iwata, H. / Awazu, Y. / Miki, H. / Hori, A. / Kamiyama, K. / Imamura, S.
History
DepositionAug 24, 2011Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Nov 2, 2011Provider: repository / Type: Initial release
Revision 1.1Mar 20, 2024Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / 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

Downloads & links

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Assembly

Deposited unit
A: Vascular endothelial growth factor receptor 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)41,2912
Polymers40,8461
Non-polymers4451
Water8,413467
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)134.340, 56.270, 52.070
Angle α, β, γ (deg.)90.00, 95.24, 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 / Fetal liver kinase 1 / FLK-1 / Kinase insert domain receptor / Protein-tyrosine kinase ...VEGFR-2 / Fetal liver kinase 1 / FLK-1 / Kinase insert domain receptor / Protein-tyrosine kinase receptor flk-1


Mass: 40845.887 Da / Num. of mol.: 1 / Fragment: KINASE DOMAIN (UNP RESIDUES 811-1169)
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: FLK1, KDR / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P35968, receptor protein-tyrosine kinase
#2: Chemical ChemComp-42Q / 1-{2-fluoro-4-[(5-methyl-5H-pyrrolo[3,2-d]pyrimidin-4-yl)oxy]phenyl}-3-[3-(trifluoromethyl)phenyl]urea


Mass: 445.370 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H15F4N5O2
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 467 / 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: 2.4 Å3/Da / Density % sol: 48.73 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 7.5
Details: 1.3M tri-sodium citrate, pH 7.5, VAPOR DIFFUSION, HANGING DROP, temperature 277K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SPring-8 / Beamline: BL32B2 / Wavelength: 1 Å
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionHighest resolution: 1.55 Å / Num. obs: 56322 / Biso Wilson estimate: 19.8 Å2

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Processing

Software
NameVersionClassification
MOLREPphasing
CNX2002refinement
d*TREKdata reduction
d*TREKdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.55→19.84 Å / Rfactor Rfree error: 0.004 / Data cutoff high absF: 1354161.36 / Data cutoff low absF: 0 / Isotropic thermal model: RESTRAINED / Cross valid method: THROUGHOUT / σ(F): 0
RfactorNum. reflection% reflectionSelection details
Rfree0.209 2738 5 %RANDOM
Rwork0.186 ---
obs-54838 97.4 %-
Solvent computationSolvent model: FLAT MODEL / Bsol: 45.6558 Å2 / ksol: 0.38605 e/Å3
Displacement parametersBiso mean: 20.2 Å2
Baniso -1Baniso -2Baniso -3
1--1.64 Å20 Å2-0.74 Å2
2--0.25 Å20 Å2
3---1.39 Å2
Refine analyze
FreeObs
Luzzati coordinate error0.19 Å0.17 Å
Luzzati d res low-5 Å
Luzzati sigma a0.1 Å0.1 Å
Refinement stepCycle: LAST / Resolution: 1.55→19.84 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2430 0 32 467 2929
Refine LS restraints
Refine-IDTypeDev idealDev ideal target
X-RAY DIFFRACTIONc_bond_d0.007
X-RAY DIFFRACTIONc_bond_d_na
X-RAY DIFFRACTIONc_bond_d_prot
X-RAY DIFFRACTIONc_angle_d
X-RAY DIFFRACTIONc_angle_d_na
X-RAY DIFFRACTIONc_angle_d_prot
X-RAY DIFFRACTIONc_angle_deg1.2
X-RAY DIFFRACTIONc_angle_deg_na
X-RAY DIFFRACTIONc_angle_deg_prot
X-RAY DIFFRACTIONc_dihedral_angle_d22.1
X-RAY DIFFRACTIONc_dihedral_angle_d_na
X-RAY DIFFRACTIONc_dihedral_angle_d_prot
X-RAY DIFFRACTIONc_improper_angle_d0.71
X-RAY DIFFRACTIONc_improper_angle_d_na
X-RAY DIFFRACTIONc_improper_angle_d_prot
X-RAY DIFFRACTIONc_mcbond_it1.111.5
X-RAY DIFFRACTIONc_mcangle_it1.742
X-RAY DIFFRACTIONc_scbond_it2.042
X-RAY DIFFRACTIONc_scangle_it3.022.5
LS refinement shellResolution: 1.55→1.65 Å / Rfactor Rfree error: 0.013 / Total num. of bins used: 6
RfactorNum. reflection% reflection
Rfree0.264 405 5 %
Rwork0.242 7648 -
obs--86.8 %
Xplor file
Refine-IDSerial noParam fileTopol file
X-RAY DIFFRACTION1protein_rep.paramprotein.top
X-RAY DIFFRACTION2dna-rna_rep.paramdna-rna.top
X-RAY DIFFRACTION3water_rep.paramwater.top
X-RAY DIFFRACTION41234567.param1234567.top

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