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- PDB-1ywn: Vegfr2 in complex with a novel 4-amino-furo[2,3-d]pyrimidine -

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Basic information

Entry
Database: PDB / ID: 1ywn
TitleVegfr2 in complex with a novel 4-amino-furo[2,3-d]pyrimidine
ComponentsVascular endothelial growth factor receptor 2VEGF receptor
KeywordsTRANSFERASE
Function / homology
Function and homology information


blood vessel endothelial cell differentiation / cellular response to hydrogen sulfide / regulation of bone development / regulation of hematopoietic progenitor cell differentiation / Signaling by membrane-tethered fusions of PDGFRA or PDGFRB / 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 / regulation of hematopoietic progenitor cell differentiation / Signaling by membrane-tethered fusions of PDGFRA or PDGFRB / 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 / embryonic hemopoiesis / vascular endothelial growth factor signaling pathway / positive regulation of mesenchymal cell proliferation / positive regulation of mitochondrial depolarization / positive regulation of mitochondrial fission / 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 / semaphorin-plexin signaling pathway / positive regulation of macroautophagy / : / 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 / angiogenesis / protein tyrosine kinase activity / 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 / Ig-like domain profile. / Immunoglobulin-like domain / Phosphorylase Kinase; domain 1 / 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-LIF / Vascular endothelial growth factor receptor 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.71 Å
AuthorsMiyazaki, Y. / Matsunaga, S. / Tang, J. / Maeda, Y. / Nakano, M. / Philippe, R.J. / Shibahara, M. / Liu, W. / Sato, H. / Wang, L. / Nolte, R.T.
Citation
Journal: Bioorg.Med.Chem.Lett. / Year: 2005
Title: Novel 4-amino-furo[2,3-d]pyrimidines as Tie-2 and VEGFR2 dual inhibitors
Authors: Miyazaki, Y. / Matsunaga, S. / Tang, J. / Maeda, Y. / Nakano, M. / Philippe, R.J. / Shibahara, M. / Liu, W. / Sato, H. / Wang, L. / Nolte, R.T.
#1: Journal: Structure / Year: 1999
Title: Crystal Structure of the kinase domain of human vascular endothelial growth factor receptor 2: a key enzyme in angiogenesis
History
DepositionFeb 18, 2005Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 23, 2005Provider: repository / Type: Initial release
Revision 1.1Apr 30, 2008Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Advisory / Version format compliance
Revision 1.3Oct 11, 2017Group: Refinement description / Category: software / Item: _software.classification / _software.name
Revision 1.4Oct 20, 2021Group: Database references / Derived calculations
Category: database_2 / struct_conn ...database_2 / struct_conn / 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_conn.pdbx_leaving_atom_flag / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id
Revision 1.5Aug 23, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model
Revision 1.6Nov 15, 2023Group: Data collection / Category: chem_comp_atom / chem_comp_bond / Item: _chem_comp_atom.atom_id / _chem_comp_bond.atom_id_2
Remark 999SEQUENCE Deletion of residues 938-987 (corresponds to dbref 940-989)

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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)36,8922
Polymers36,3551
Non-polymers5371
Water3,765209
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)37.953, 95.595, 95.803
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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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


Mass: 36354.719 Da / Num. of mol.: 1 / Fragment: Kinase Domain / Mutation: E990V, Deletion of residues 940-989
Source method: isolated from a genetically manipulated source
Details: E990V, Deletion of residues 940-989 / Source: (gene. exp.) Homo sapiens (human) / Gene: KDR, FLK1 / Cell line (production host): SF9 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P35968, EC: 2.7.1.112
#2: Chemical ChemComp-LIF / N-{4-[4-AMINO-6-(4-METHOXYPHENYL)FURO[2,3-D]PYRIMIDIN-5-YL]PHENYL}-N'-[2-FLUORO-5-(TRIFLUOROMETHYL)PHENYL]UREA / N-(4-{4-AMINO-6-[4-(METHYLOXY)PHENYL]FURO[2,3-D]PYRIMIDIN-5-YL}PHENYL)-N'-[2-FLUORO-5-(TRIFLUOROMETHYL)PHENYL]UREA


Mass: 537.465 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C27H19F4N5O3
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 209 / 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: 2.39 Å3/Da / Density % sol: 48.54 %
Crystal growMethod: vapor diffusion, hanging drop / Details: VAPOR DIFFUSION, HANGING DROP

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: MARRESEARCH / Detector: CCD / Date: May 1, 2001
RadiationMonochromator: Si 111 / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.7→50 Å / Num. obs: 37357 / % possible obs: 94.7 % / Observed criterion σ(F): -3 / Observed criterion σ(I): -3 / Redundancy: 6.43 % / Biso Wilson estimate: 25.2 Å2 / Rmerge(I) obs: 0.047 / Net I/σ(I): 31.38
Reflection shellResolution: 1.7→1.76 Å / Redundancy: 4.3 % / Rmerge(I) obs: 0.383 / Mean I/σ(I) obs: 2.63 / Num. unique all: 2767 / % possible all: 71.8

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Processing

Software
NameVersionClassification
REFMAC5.2.0005refinement
MAR345data collection
SCALEPACKdata scaling
AMoREphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: pdb entry 1Y6A

1y6a


Resolution: 1.71→47.89 Å / Cor.coef. Fo:Fc: 0.953 / Cor.coef. Fo:Fc free: 0.944 / SU B: 4.206 / SU ML: 0.071 / TLS residual ADP flag: LIKELY RESIDUAL / Cross valid method: THROUGHOUT / σ(F): -3 / ESU R: 0.113 / ESU R Free: 0.107 / Stereochemistry target values: MAXIMUM LIKELIHOOD
RfactorNum. reflection% reflectionSelection details
Rfree0.23005 1139 3.1 %RANDOM
Rwork0.20488 ---
obs0.20564 35577 95.19 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: BABINET MODEL WITH MASK
Displacement parametersBiso mean: 32.124 Å2
Baniso -1Baniso -2Baniso -3
1-0.12 Å20 Å20 Å2
2--1.12 Å20 Å2
3----1.24 Å2
Refinement stepCycle: LAST / Resolution: 1.71→47.89 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2264 0 39 209 2512
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0120.0222360
X-RAY DIFFRACTIONr_bond_other_d0.0020.022148
X-RAY DIFFRACTIONr_angle_refined_deg1.4851.9913195
X-RAY DIFFRACTIONr_angle_other_deg0.82334983
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.9225277
X-RAY DIFFRACTIONr_dihedral_angle_2_deg32.68322.981104
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.75215409
X-RAY DIFFRACTIONr_dihedral_angle_4_deg16.2881518
X-RAY DIFFRACTIONr_chiral_restr0.0850.2342
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.022570
X-RAY DIFFRACTIONr_gen_planes_other0.0050.02506
X-RAY DIFFRACTIONr_nbd_refined0.2190.2477
X-RAY DIFFRACTIONr_nbd_other0.1880.22072
X-RAY DIFFRACTIONr_nbtor_refined0.1880.21165
X-RAY DIFFRACTIONr_nbtor_other0.0860.21208
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.210.2136
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.2290.213
X-RAY DIFFRACTIONr_symmetry_vdw_other0.2050.261
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.1680.223
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it1.2131.51805
X-RAY DIFFRACTIONr_mcbond_other0.2181.5567
X-RAY DIFFRACTIONr_mcangle_it1.36522255
X-RAY DIFFRACTIONr_scbond_it2.21431152
X-RAY DIFFRACTIONr_scangle_it3.0674.5940
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.71→1.754 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.259 63 -
Rwork0.227 2005 -
obs--73.88 %
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
11.95580.1241-0.57162.4370.49252.93760.02140.07240.0571-0.06120.0050.2199-0.0261-0.0804-0.0265-0.1108-0.00110.0002-0.008-0.012-0.07472.11834.2236.18
21.72370.27350.50841.66320.90582.6364-0.0551-0.0696-0.04340.061-0.03670.06960.0962-0.2470.0918-0.1049-0.01550.00560.0431-0.0367-0.1027.68441.43132.389
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
1X-RAY DIFFRACTION1AA818 - 92015 - 117
2X-RAY DIFFRACTION2AA921 - 1169118 - 316

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