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- PDB-4ag8: CRYSTAL STRUCTURE OF THE VEGFR2 KINASE DOMAIN IN COMPLEX WITH AXI... -

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Basic information

Entry
Database: PDB / ID: 4ag8
TitleCRYSTAL STRUCTURE OF THE VEGFR2 KINASE DOMAIN IN COMPLEX WITH AXITINIB (AG-013736) (N-Methyl-2-(3-((E)-2-pyridin-2-yl-vinyl)-1H- indazol-6-ylsulfanyl)-benzamide)
ComponentsVASCULAR ENDOTHELIAL GROWTH FACTOR RECEPTOR 2
KeywordsTRANSFERASE / ANGIOGENESIS / NUCLEOTIDE-BINDING / INHIBITOR / PHOSPHORYLATION / TRANSMEMBRANE
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
AXITINIB / Vascular endothelial growth factor receptor 2
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 1.95 Å
AuthorsMcTigue, M. / Wickersham, J. / Pinko, C. / Kania, R.S. / Bender, S.
CitationJournal: Proc.Natl.Acad.Sci.USA / Year: 2012
Title: Molecular Conformations, Interactions, and Properties Associated with Drug Efficiency and Clinical Performance Among Vegfr Tk Inhibitors.
Authors: Mctigue, M. / Murray, B.W. / Chen, J.H. / Deng, Y. / Solowiej, J. / Kania, R.S.
History
DepositionJan 24, 2012Deposition site: PDBE / Processing site: PDBE
Revision 1.0Sep 26, 2012Provider: repository / Type: Initial release
Revision 1.1Nov 14, 2012Group: Database references / Other
Revision 1.2Jun 28, 2017Group: Data collection / Category: diffrn_source / Item: _diffrn_source.type
Revision 1.3May 8, 2019Group: Data collection / Experimental preparation
Category: database_PDB_rev / database_PDB_rev_record / exptl_crystal_grow
Item: _exptl_crystal_grow.method
Revision 1.4Dec 20, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Other / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_database_status / pdbx_initial_refinement_model / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_database_status.status_code_sf / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id
Revision 1.5Aug 7, 2024Group: Data collection / Category: chem_comp_atom / chem_comp_bond
Item: _chem_comp_atom.atom_id / _chem_comp_bond.atom_id_1 ..._chem_comp_atom.atom_id / _chem_comp_bond.atom_id_1 / _chem_comp_bond.atom_id_2 / _chem_comp_bond.value_order

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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)36,5812
Polymers36,1951
Non-polymers3861
Water5,873326
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)135.660, 57.221, 51.829
Angle α, β, γ (deg.)90.00, 93.44, 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 / KDR / PROTEIN-TYROSINE ...VEGFR-2 / FETAL LIVER KINASE 1 / FLK-1 / KINASE INSERT DOMAIN RECEPTOR / KDR / PROTEIN-TYROSINE KINASE RECEPTOR FLK-1 / CD309


Mass: 36194.762 Da / Num. of mol.: 1 / Fragment: KINASE DOMAIN, RESIDUES 806-940,990-1171 / Mutation: YES
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Plasmid: PACSG2 / Cell line (production host): SF9 / Production host: SPODOPTERA FRUGIPERDA (fall armyworm)
References: UniProt: P35968, receptor protein-tyrosine kinase
#2: Chemical ChemComp-AXI / AXITINIB / N-METHYL-2-(3-((E)-2-PYRIDIN-2-YL-VINYL)-1H-INDAZOL-6-YLSULFANYL)-BENZAMIDE


Mass: 386.470 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C22H18N4OS / Comment: inhibitor*YM
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 326 / Source method: isolated from a natural source / Formula: H2O
Compound detailsENGINEERED RESIDUE IN CHAIN A, GLU 990 TO VAL

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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: 2.87 Å3/Da / Density % sol: 57.14 % / Description: NONE
Crystal growMethod: vapor diffusion, hanging drop / pH: 7.5
Details: CRYSTALS WERE GROWN AT 4 OR 13 C BY THE HANGING DROP VAPOR DIFFUSION BY MIXING 2 MICORLITERS OF PROTEIN-INHIBITOR COMPLEX SOLUTION WITH 2 MICROLITERS OF MOTHER LIQUOR (100 MM HEPES (PH 7.5), ...Details: CRYSTALS WERE GROWN AT 4 OR 13 C BY THE HANGING DROP VAPOR DIFFUSION BY MIXING 2 MICORLITERS OF PROTEIN-INHIBITOR COMPLEX SOLUTION WITH 2 MICROLITERS OF MOTHER LIQUOR (100 MM HEPES (PH 7.5), 200 MM AMMONIUM SULFATE, 5% (V/V) MPD, AND 15-20% (W/V) POLYETHYLENE GLYCOL (MW = 6000)). BEFORE SEALING THE COVERSLIPS ABOVE THE RESERVOIRS, BETA-MERCAPTOETHANOL WAS ADDED TO THE RESERVOIRS TO A FINAL CONCENTRATION OF 60 MM. THIS PROCEDURE PRODUCED MICROCRYSTALS THAT WERE SUBSEQUENTLY USED TO SEED MORE CRYSTALLIZATION DROPS AFTER 12-18 HOURS OF EQUILIBRATION.

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Data collection

DiffractionMean temperature: 87 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU RU200 / Wavelength: 1.5418
DetectorType: MARRESEARCH / Detector: IMAGE PLATE / Date: Dec 12, 1999 / Details: MIRRORS
RadiationMonochromator: NI FILTER / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 1.95→20 Å / Num. obs: 28556 / % possible obs: 99 % / Observed criterion σ(I): 2 / Redundancy: 2.7 % / Rmerge(I) obs: 0.05 / Net I/σ(I): 23
Reflection shellResolution: 1.95→2.02 Å / Rmerge(I) obs: 0.18 / Mean I/σ(I) obs: 7.7 / % possible all: 97.7

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Processing

Software
NameVersionClassification
REFMAC5.1.24refinement
DENZOdata reduction
SCALEPACKdata scaling
EPMRphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 1VR2

1vr2


Resolution: 1.95→19.84 Å / Cor.coef. Fo:Fc: 0.939 / Cor.coef. Fo:Fc free: 0.914 / SU B: 3.01 / SU ML: 0.09 / Cross valid method: THROUGHOUT / ESU R: 0.16 / ESU R Free: 0.153 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS.
RfactorNum. reflection% reflectionSelection details
Rfree0.2415 1450 5.1 %RANDOM
Rwork0.19493 ---
obs0.19726 27105 98.75 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: BABINET MODEL WITH MASK
Displacement parametersBiso mean: 25.15 Å2
Baniso -1Baniso -2Baniso -3
1-0.21 Å20 Å2-0.34 Å2
2--0.03 Å20 Å2
3----0.28 Å2
Refinement stepCycle: LAST / Resolution: 1.95→19.84 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2381 0 28 326 2735
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0090.0212471
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.1041.973337
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.4395294
X-RAY DIFFRACTIONr_dihedral_angle_2_deg
X-RAY DIFFRACTIONr_dihedral_angle_3_deg
X-RAY DIFFRACTIONr_dihedral_angle_4_deg
X-RAY DIFFRACTIONr_chiral_restr0.0890.2355
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.021872
X-RAY DIFFRACTIONr_gen_planes_other
X-RAY DIFFRACTIONr_nbd_refined0.1870.21171
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1370.2264
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.1990.238
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.1360.214
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it0.581.51473
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it1.13322373
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it1.6713998
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it2.8184.5964
X-RAY DIFFRACTIONr_scangle_other
X-RAY DIFFRACTIONr_long_range_B_refined
X-RAY DIFFRACTIONr_long_range_B_other
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.953→2.003 Å / Total num. of bins used: 20 /
RfactorNum. reflection
Rfree0.249 98
Rwork0.192 1874

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