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- PDB-3cpc: Crystal structure of the VEGFR2 kinase domain in complex with a p... -

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Basic information

Entry
Database: PDB / ID: 3cpc
TitleCrystal structure of the VEGFR2 kinase domain in complex with a pyridone inhibitor
ComponentsVascular endothelial growth factor receptor 2
KeywordsTRANSFERASE / receptor tyrosine kinase / 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 / 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 ...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 / 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 / post-embryonic camera-type eye morphogenesis / endothelial cell differentiation / positive regulation of vasculogenesis / mesenchymal cell proliferation / 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 mesenchymal cell proliferation / positive regulation of endothelial cell chemotaxis / 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 / 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 / cell fate commitment / vasculogenesis / calcium ion homeostasis / Integrin cell surface interactions / coreceptor activity / vascular endothelial growth factor receptor signaling pathway / negative regulation of endothelial cell apoptotic process / peptidyl-tyrosine autophosphorylation / ovarian follicle development / positive regulation of endothelial cell proliferation / cell surface receptor protein tyrosine kinase signaling pathway / 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 / 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 / positive regulation of ERK1 and ERK2 cascade / early endosome / 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 / 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-C52 / Vascular endothelial growth factor receptor 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 2.4 Å
AuthorsWhittington, D.A. / Long, A.M. / Rose, P. / Gu, Y. / Zhao, H.
CitationJournal: J.Med.Chem. / Year: 2008
Title: Discovery of Aryl Aminoquinazoline Pyridones as Potent, Selective, and Orally Efficacious Inhibitors of Receptor Tyrosine Kinase c-Kit.
Authors: Hu, E. / Tasker, A. / White, R.D. / Kunz, R.K. / Human, J. / Chen, N. / Burli, R. / Hungate, R. / Novak, P. / Itano, A. / Zhang, X. / Yu, V. / Nguyen, Y. / Tudor, Y. / Plant, M. / Flynn, S. ...Authors: Hu, E. / Tasker, A. / White, R.D. / Kunz, R.K. / Human, J. / Chen, N. / Burli, R. / Hungate, R. / Novak, P. / Itano, A. / Zhang, X. / Yu, V. / Nguyen, Y. / Tudor, Y. / Plant, M. / Flynn, S. / Xu, Y. / Meagher, K.L. / Whittington, D.A. / Ng, G.Y.
History
DepositionMar 31, 2008Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 17, 2008Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Advisory / Refinement description / Version format compliance
Revision 1.2Jul 26, 2017Group: Refinement description / Source and taxonomy / Category: entity_src_gen / software
Revision 1.3Jun 13, 2018Group: Data collection / Database references / Category: struct_ref / struct_ref_seq / struct_ref_seq_dif
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
B: Vascular endothelial growth factor receptor 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)73,3624
Polymers72,5692
Non-polymers7932
Water2,036113
1
A: Vascular endothelial growth factor receptor 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,6812
Polymers36,2851
Non-polymers3961
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Vascular endothelial growth factor receptor 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,6812
Polymers36,2851
Non-polymers3961
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)55.361, 66.865, 89.858
Angle α, β, γ (deg.)90.00, 93.352, 90.00
Int Tables number4
Space group name H-MP1211

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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: 36284.586 Da / Num. of mol.: 2 / Fragment: PROTEIN KINASE DOMAIN, RESIDUES 940-989 DELETED / Mutation: C817A, V916T, E990V
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-C52 / 3-(2-aminoquinazolin-6-yl)-4-methyl-1-[3-(trifluoromethyl)phenyl]pyridin-2(1H)-one


Mass: 396.365 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C21H15F3N4O
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 113 / Source method: isolated from a natural source / Formula: H2O
Nonpolymer detailsTYR1054 AND TYR1059 WERE PHOSPHORYLATED BY AN AUTOPHOSPHORYLATION REACTION RUN ON THE PROTEIN PRIOR ...TYR1054 AND TYR1059 WERE PHOSPHORYLATED BY AN AUTOPHOSPHORYLATION REACTION RUN ON THE PROTEIN PRIOR TO CRYSTALLIZATION. THE PHOSPHORYLATED TYR IS REPRESENTED BY PTR, PHOSPHONOTYROSINE, PTR1054 AND PTR1059. THESE RESIDUES ARE PART OF THE KINASE ACTIVATION LOOP AND THEY ARE DISORDERED IN THE STRUCTURE AND CONSEQUENTLY NOT SEEN IN THE ELECTRON DENSITY.

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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: 2.29 Å3/Da / Density % sol: 46.24 %
Crystal growTemperature: 277 K / Method: vapor diffusion / pH: 8
Details: PEG 5000 MME, HEPES, ammonium sulfate, sodium chloride, isopropanol, beta-mercaptoethanol, pH 8.0, VAPOR DIFFUSION, temperature 277K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 31-ID / Wavelength: 0.9793 Å
DetectorType: MAR CCD 165 mm / Detector: CCD
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9793 Å / Relative weight: 1
ReflectionResolution: 2.4→30 Å / Num. all: 25592 / Num. obs: 24082 / % possible obs: 94.1 % / Observed criterion σ(I): -3 / Redundancy: 5.7 % / Rmerge(I) obs: 0.084 / Χ2: 0.985 / Net I/σ(I): 17.8
Reflection shellResolution: 2.4→2.49 Å / Redundancy: 5.5 % / Rmerge(I) obs: 0.415 / Mean I/σ(I) obs: 3.9 / Num. unique all: 2526 / Χ2: 1.011 / % possible all: 99.9

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Processing

Software
NameVersionClassificationNB
SCALEPACKdata scaling
REFMACrefinement
PDB_EXTRACT1.401data extraction
DENZOdata reduction
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 2.4→30 Å / Cor.coef. Fo:Fc: 0.931 / Cor.coef. Fo:Fc free: 0.893 / SU B: 17.089 / SU ML: 0.205 / SU R Cruickshank DPI: 0.563 / TLS residual ADP flag: LIKELY RESIDUAL / Cross valid method: THROUGHOUT / ESU R Free: 0.307
RfactorNum. reflection% reflectionSelection details
Rfree0.272 1422 5.9 %RANDOM
Rwork0.218 ---
all0.221 24161 --
obs-22627 93.65 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 35.472 Å2
Baniso -1Baniso -2Baniso -3
1--1.24 Å20 Å20.33 Å2
2---0.89 Å20 Å2
3---2.17 Å2
Refinement stepCycle: LAST / Resolution: 2.4→30 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4409 0 58 113 4580
Refine LS restraints
Refine-IDTypeDev idealNumberWeight
X-RAY DIFFRACTIONr_bond_refined_d0.00745840.022
X-RAY DIFFRACTIONr_angle_refined_deg0.93362041.977
X-RAY DIFFRACTIONr_dihedral_angle_1_deg4.9855385
X-RAY DIFFRACTIONr_dihedral_angle_2_deg32.39520323.054
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.86980015
X-RAY DIFFRACTIONr_dihedral_angle_4_deg14.4843115
X-RAY DIFFRACTIONr_chiral_restr0.0616710.2
X-RAY DIFFRACTIONr_gen_planes_refined0.00234390.02
X-RAY DIFFRACTIONr_nbd_refined0.16219920.2
X-RAY DIFFRACTIONr_nbtor_refined0.29530920.2
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1121840.2
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.133460.2
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.166110.2
X-RAY DIFFRACTIONr_mcbond_it0.57428272
X-RAY DIFFRACTIONr_mcangle_it143983
X-RAY DIFFRACTIONr_scbond_it0.67720713
X-RAY DIFFRACTIONr_scangle_it1.07718064.5
LS refinement shellResolution: 2.403→2.465 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.328 103 -
Rwork0.265 1631 -
obs--94.65 %
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)
11.2190.01850.06550.1251-0.00310.0065-0.0249-0.057-0.0345-0.03910.0143-0.0198-0.00290.00730.0106-0.02770.001-0.0147-0.0257-0.0216-0.01634.701836.337232.706
22.01560.96830.4121.23240.26090.9448-0.13340.09440.0928-0.1790.0016-0.0620.1252-0.01480.13190.0130.01690.0538-0.09320.0082-0.085520.28562.243112.4638
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A820 - 1178
2X-RAY DIFFRACTION2B820 - 1165

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