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

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Basic information

Entry
Database: PDB / ID: 3cjg
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


cellular response to hydrogen sulfide / blood vessel endothelial cell differentiation / regulation of bone development / Signaling by membrane-tethered fusions of PDGFRA or PDGFRB / post-embryonic camera-type eye morphogenesis / vascular endothelial growth factor binding / Neurophilin interactions with VEGF and VEGFR / vascular endothelial growth factor receptor-2 signaling pathway / VEGF binds to VEGFR leading to receptor dimerization / endothelium development ...cellular response to hydrogen sulfide / blood vessel endothelial cell differentiation / regulation of bone development / Signaling by membrane-tethered fusions of PDGFRA or PDGFRB / post-embryonic camera-type eye morphogenesis / vascular endothelial growth factor binding / Neurophilin interactions with VEGF and VEGFR / vascular endothelial growth factor receptor-2 signaling pathway / VEGF binds to VEGFR leading to receptor dimerization / endothelium development / endocardium development / vascular wound healing / regulation of hematopoietic progenitor cell differentiation / vascular endothelial growth factor receptor activity / positive regulation of vasculogenesis / endothelial cell differentiation / lymph vessel development / mesenchymal cell proliferation / positive regulation of BMP signaling pathway / surfactant homeostasis / cell migration involved in sprouting angiogenesis / positive regulation of mesenchymal cell proliferation / epithelial cell maturation / anchoring junction / positive regulation of positive chemotaxis / embryonic hemopoiesis / vascular endothelial growth factor signaling pathway / positive regulation of endothelial cell chemotaxis / lung alveolus development / positive regulation of cell migration involved in sprouting angiogenesis / branching involved in blood vessel morphogenesis / positive regulation of mitochondrial fission / positive regulation of mitochondrial depolarization / positive regulation of stem cell proliferation / regulation of MAPK cascade / positive regulation of nitric-oxide synthase biosynthetic process / growth factor binding / sorting endosome / positive regulation of focal adhesion assembly / positive regulation of macroautophagy / semaphorin-plexin signaling pathway / cell fate commitment / positive regulation of blood vessel endothelial cell migration / cellular response to vascular endothelial growth factor stimulus / Integrin cell surface interactions / vasculogenesis / vascular endothelial growth factor receptor signaling pathway / negative regulation of endothelial cell apoptotic process / coreceptor activity / calcium ion homeostasis / peptidyl-tyrosine autophosphorylation / cell surface receptor protein tyrosine kinase signaling pathway / ovarian follicle development / positive regulation of endothelial cell proliferation / transmembrane receptor protein tyrosine kinase activity / positive regulation of endothelial cell migration / epithelial cell proliferation / VEGFR2 mediated cell proliferation / stem cell proliferation / Hsp90 protein binding / receptor protein-tyrosine kinase / VEGFA-VEGFR2 Pathway / peptidyl-tyrosine phosphorylation / positive regulation of angiogenesis / integrin binding / cell migration / cell junction / regulation of cell shape / protein tyrosine kinase activity / angiogenesis / negative regulation of neuron apoptotic process / protein autophosphorylation / positive regulation of MAPK cascade / positive regulation of ERK1 and ERK2 cascade / early endosome / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / receptor complex / 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 / 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 / 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 ...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 / 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-KIM / Vascular endothelial growth factor receptor 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.25 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)36,0564
Polymers35,4441
Non-polymers6133
Water2,090116
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)37.700, 95.540, 97.010
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: 35443.906 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.: 2 / Source method: obtained synthetically / Formula: SO4
#3: Chemical ChemComp-KIM / N~4~-methyl-N~4~-(3-methyl-1H-indazol-6-yl)-N~2~-(3,4,5-trimethoxyphenyl)pyrimidine-2,4-diamine


Mass: 420.464 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C22H24N6O3
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 116 / 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: 2.46 Å3/Da / Density % sol: 50.09 %
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: 2.25→40 Å / Num. all: 17125 / Num. obs: 16998 / % possible obs: 99.3 % / Observed criterion σ(F): -3 / Observed criterion σ(I): 0 / Redundancy: 6.9 % / Biso Wilson estimate: 40.6 Å2 / Rmerge(I) obs: 0.046 / Net I/σ(I): 40
Reflection shellResolution: 2.25→2.33 Å / Rmerge(I) obs: 0.401 / Mean I/σ(I) obs: 2.76 / % possible all: 95

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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: 2.25→19.95 Å / Cor.coef. Fo:Fc: 0.949 / Cor.coef. Fo:Fc free: 0.927 / SU B: 13.266 / SU ML: 0.17 / TLS residual ADP flag: LIKELY RESIDUAL / Cross valid method: THROUGHOUT / ESU R: 0.287 / ESU R Free: 0.223 / Stereochemistry target values: MAXIMUM LIKELIHOOD
RfactorNum. reflection% reflectionSelection details
Rfree0.25316 544 3.2 %RANDOM
Rwork0.20733 ---
obs0.20875 16534 99.08 %-
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: 47.869 Å2
Baniso -1Baniso -2Baniso -3
1-2.98 Å20 Å20 Å2
2---2.77 Å20 Å2
3----0.21 Å2
Refinement stepCycle: LAST / Resolution: 2.25→19.95 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2249 0 41 116 2406
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0110.0222401
X-RAY DIFFRACTIONr_bond_other_d0.0010.021655
X-RAY DIFFRACTIONr_angle_refined_deg1.2771.9823250
X-RAY DIFFRACTIONr_angle_other_deg0.86834010
X-RAY DIFFRACTIONr_dihedral_angle_1_deg18.4585.204294
X-RAY DIFFRACTIONr_dihedral_angle_2_deg36.53622.991107
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.8715412
X-RAY DIFFRACTIONr_dihedral_angle_4_deg17.8071519
X-RAY DIFFRACTIONr_chiral_restr0.0730.2347
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.022681
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02511
X-RAY DIFFRACTIONr_nbd_refined0.2080.2505
X-RAY DIFFRACTIONr_nbd_other0.1880.21744
X-RAY DIFFRACTIONr_nbtor_refined0.1790.21189
X-RAY DIFFRACTIONr_nbtor_other0.0850.21187
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1320.296
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.0660.24
X-RAY DIFFRACTIONr_symmetry_vdw_other0.1910.221
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.180.28
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it0.6151.51479
X-RAY DIFFRACTIONr_mcbond_other0.1111.5579
X-RAY DIFFRACTIONr_mcangle_it1.0622315
X-RAY DIFFRACTIONr_scbond_it1.39831068
X-RAY DIFFRACTIONr_scangle_it2.0494.5935
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.25→2.312 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.25 38 -
Rwork0.273 1104 -
obs--91.51 %
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)
13.4051-1.0658-1.67926.03340.46945.82860.1408-0.30650.1560.47260.0434-0.4943-0.26880.8209-0.1843-0.3159-0.0432-0.0016-0.1604-0.0332-0.21467.61429.84511.354
22.35860.3952-1.05537.033.18327.3804-0.07820.02730.0475-0.33630.2016-0.3176-0.22030.4765-0.1233-0.3275-0.00230.0305-0.2372-0.0486-0.19131.76855.68818.451
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A814 - 918
2X-RAY DIFFRACTION2A919 - 1166

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