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- PDB-3cjf: Crystal structure of VEGFR2 in complex with a 3,4,5-trimethoxy an... -

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Basic information

Entry
Database: PDB / ID: 3cjf
TitleCrystal structure of VEGFR2 in complex with a 3,4,5-trimethoxy aniline containing pyrimidine
ComponentsVascular endothelial growth factor receptor 2
KeywordsTRANSFERASE / Vascular endothelial growth factor receptor 2. vegfr-2 / kinase insert domain receptor / protein-tyrosine kinase receptor flk-1 / Angiogenesis / ATP-binding / Developmental protein / Differentiation / Glycoprotein / Host-virus interaction / Immunoglobulin domain / Membrane / Nucleotide-binding / Phosphoprotein / 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 / 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-SAV / Vascular endothelial growth factor receptor 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.15 Å
AuthorsNolte, R.T.
CitationJournal: J.Med.Chem. / Year: 2008
Title: Discovery of 5-[[4-[(2,3-dimethyl-2H-indazol-6-yl)methylamino]-2-pyrimidinyl]amino]-2-methyl-benzenesulfonamide (Pazopanib), a novel and potent vascular endothelial growth factor receptor inhibitor.
Authors: Harris, P.A. / Boloor, A. / Cheung, M. / Kumar, R. / Crosby, R.M. / Davis-Ward, R.G. / Epperly, A.H. / Hinkle, K.W. / Hunter, R.N. / Johnson, J.H. / Knick, V.B. / Laudeman, C.P. / Luttrell, ...Authors: Harris, P.A. / Boloor, A. / Cheung, M. / Kumar, R. / Crosby, R.M. / Davis-Ward, R.G. / Epperly, A.H. / Hinkle, K.W. / Hunter, R.N. / Johnson, J.H. / Knick, V.B. / Laudeman, C.P. / Luttrell, D.K. / Mook, R.A. / Nolte, R.T. / Rudolph, S.K. / Szewczyk, J.R. / Truesdale, A.T. / Veal, J.M. / Wang, L. / Stafford, J.A.
History
DepositionMar 12, 2008Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 7, 2008Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Advisory / Refinement description / Version format compliance
Revision 1.2Aug 23, 2017Group: Source and taxonomy / Category: entity_src_gen
Revision 1.3Oct 25, 2017Group: Refinement description / Category: software / Item: _software.name
Revision 1.4Aug 30, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / struct_conn / 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_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id
Revision 1.5Nov 15, 2023Group: Data collection / Category: chem_comp_atom / chem_comp_bond / Item: _chem_comp_atom.atom_id / _chem_comp_bond.atom_id_2
Revision 1.6Oct 30, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature / Item: _pdbx_entry_details.has_protein_modification

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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)36,2836
Polymers35,4921
Non-polymers7915
Water1,47782
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)37.435, 94.742, 96.797
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 / VEGFR-2 / Kinase insert domain receptor / Protein-tyrosine kinase receptor Flk-1 / CD309 antigen


Mass: 35491.906 Da / Num. of mol.: 1 / Fragment: kinase domain; residues 806-939 and 994-1168
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Description: KID insert removed / Gene: KDR, FLK1 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P35968, receptor protein-tyrosine kinase
#2: Chemical
ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: SO4
#3: Chemical ChemComp-SAV / N~4~-(3-methyl-1H-indazol-6-yl)-N~2~-(3,4,5-trimethoxyphenyl)pyrimidine-2,4-diamine


Mass: 406.438 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H22N6O3
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 82 / Source method: isolated from a natural source / Formula: H2O
Has protein modificationY
Sequence detailsK -> N CONFLICT IN UNP ENTRY P35968

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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: 2.42 Å3/Da / Density % sol: 49.14 %
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: MAR CCD 165 mm / Detector: CCD / Date: Mar 1, 2000
RadiationMonochromator: Si111 / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.15→40 Å / Num. all: 18647 / Num. obs: 18596 / % possible obs: 96.3 % / Observed criterion σ(F): -3 / Observed criterion σ(I): 0 / Redundancy: 6.6 % / Biso Wilson estimate: 43.5 Å2 / Rmerge(I) obs: 0.042 / Net I/σ(I): 42.4
Reflection shellResolution: 2.15→2.23 Å / Rmerge(I) obs: 0.423 / Mean I/σ(I) obs: 2.3 / % possible all: 74.3

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Processing

Software
NameVersionClassification
REFMAC5.2.0019refinement
MAR345data collection
HKL-2000data reduction
SCALEPACKdata scaling
AMoREphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: Unliganded Vegfr2 kinase domain solved in house - similar to pdb entry 1VR2

1vr2


Resolution: 2.15→34.92 Å / Cor.coef. Fo:Fc: 0.956 / Cor.coef. Fo:Fc free: 0.932 / SU B: 12.474 / SU ML: 0.161 / TLS residual ADP flag: LIKELY RESIDUAL / Cross valid method: THROUGHOUT / ESU R: 0.243 / ESU R Free: 0.209 / Stereochemistry target values: MAXIMUM LIKELIHOOD
RfactorNum. reflection% reflectionSelection details
Rfree0.25813 601 3.2 %RANDOM
Rwork0.20352 ---
obs0.20518 17994 96.16 %-
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: 62.689 Å2
Baniso -1Baniso -2Baniso -3
1-2.38 Å20 Å20 Å2
2--0.72 Å20 Å2
3----3.1 Å2
Refinement stepCycle: LAST / Resolution: 2.15→34.92 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2229 0 50 82 2361
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0110.0222401
X-RAY DIFFRACTIONr_bond_other_d0.0010.021660
X-RAY DIFFRACTIONr_angle_refined_deg1.3091.9863250
X-RAY DIFFRACTIONr_angle_other_deg0.89634022
X-RAY DIFFRACTIONr_dihedral_angle_1_deg22.5385.397302
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.31122.788104
X-RAY DIFFRACTIONr_dihedral_angle_3_deg17.22415411
X-RAY DIFFRACTIONr_dihedral_angle_4_deg18.2431520
X-RAY DIFFRACTIONr_chiral_restr0.080.2346
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.022678
X-RAY DIFFRACTIONr_gen_planes_other0.0020.02511
X-RAY DIFFRACTIONr_nbd_refined0.2250.2475
X-RAY DIFFRACTIONr_nbd_other0.1910.21681
X-RAY DIFFRACTIONr_nbtor_refined0.1790.21158
X-RAY DIFFRACTIONr_nbtor_other0.0860.21253
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.150.288
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.1720.214
X-RAY DIFFRACTIONr_symmetry_vdw_other0.1570.230
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.2270.26
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it0.6341.51490
X-RAY DIFFRACTIONr_mcbond_other0.1271.5579
X-RAY DIFFRACTIONr_mcangle_it1.00222317
X-RAY DIFFRACTIONr_scbond_it1.39331067
X-RAY DIFFRACTIONr_scangle_it2.0724.5933
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.15→2.21 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.324 34 -
Rwork0.264 948 -
obs--69.5 %
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)
14.14750.5389-1.00136.1376-1.26387.2860.0290.0018-0.17990.223-0.0372-0.61850.51970.51720.0083-0.37680.0389-0.0285-0.2480.009-0.287216.93712.7385.713
23.11881.30410.49636.5802-4.09819.2842-0.12940.01950.09330.4458-0.0262-0.2271-0.83590.34530.1556-0.1657-0.06820.0062-0.21430.0642-0.299211.1096.24332.628
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A815 - 918
2X-RAY DIFFRACTION2A919 - 1166

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