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- PDB-2xir: Crystal structure of the VEGFR2 kinase domain in complex with PF-... -

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Basic information

Entry
Database: PDB / ID: 2xir
TitleCrystal structure of the VEGFR2 kinase domain in complex with PF- 00337210 (N,2-dimethyl-6-(7-(2-morpholinoethoxy)quinolin-4-yloxy) benzofuran-3-carboxamide)
ComponentsVASCULAR ENDOTHELIAL GROWTH FACTOR RECEPTOR 2VEGF receptor
KeywordsTRANSFERASE / ANGIOGENESIS / NUCLEOTIDE-BINDING / INHIBITOR / PHOSPHORYLATION / RECEPTOR / 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 / regulation of hematopoietic progenitor cell differentiation / 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 / Signaling by membrane-tethered fusions of PDGFRA or PDGFRB / regulation of hematopoietic progenitor cell differentiation / 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 / cell migration involved in sprouting angiogenesis / anchoring junction / positive regulation of positive chemotaxis / vascular endothelial growth factor signaling pathway / embryonic hemopoiesis / positive regulation of mesenchymal cell proliferation / positive regulation of mitochondrial depolarization / branching involved in blood vessel morphogenesis / positive regulation of mitochondrial fission / 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 / : / cellular response to vascular endothelial growth factor stimulus / positive regulation of blood vessel endothelial cell migration / 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 / epithelial cell proliferation / VEGFR2 mediated 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 / 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 / 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 / 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-00J / Vascular endothelial growth factor receptor 2
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.5 Å
AuthorsMcTigue, M. / Wickersham, J. / Pinko, C. / Hong, Y. / Marrone, T.
CitationJournal: To be Published
Title: Discovery of the Selective Vegfr Inhibitor Pf- 00337210
Authors: Mctigue, M. / Wickersham, J. / Marrone, T.
History
DepositionJun 30, 2010Deposition site: PDBE / Processing site: PDBE
Revision 1.0Apr 13, 2011Provider: repository / Type: Initial release
Revision 1.1May 8, 2011Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Version format compliance
Revision 1.3May 8, 2019Group: Data collection / Derived calculations ...Data collection / Derived calculations / Experimental preparation / Other
Category: database_PDB_rev / database_PDB_rev_record ...database_PDB_rev / database_PDB_rev_record / exptl_crystal_grow / pdbx_database_proc / pdbx_database_status / pdbx_struct_special_symmetry
Item: _exptl_crystal_grow.method / _exptl_crystal_grow.temp / _pdbx_database_status.recvd_author_approval
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

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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)36,6562
Polymers36,1951
Non-polymers4621
Water6,071337
1


  • Idetical with deposited unit
  • defined by software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)135.267, 56.827, 52.187
Angle α, β, γ (deg.)90.00, 94.18, 90.00
Int Tables number5
Space group name H-MC121
Components on special symmetry positions
IDModelComponents
11A-3293-

HOH

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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 / FETAL LIVER ...VEGFR-2 / KINASE INSERT DOMAIN RECEPTOR / PROTEIN-TYROSINE KINASE RECEPTOR FLK-1 / FETAL LIVER KINASE 1 / FLK-1 / CD309


Mass: 36194.762 Da / Num. of mol.: 1 / Fragment: KINASE DOMAIN, RESIDUES 806-939,990-1171 / Mutation: YES / Source method: obtained synthetically / Source: (synth.) HOMO SAPIENS (human)
References: UniProt: P35968, receptor protein-tyrosine kinase
#2: Chemical ChemComp-00J / N,2-DIMETHYL-6-{[7-(2-MORPHOLIN-4-YLETHOXY)QUINOLIN-4-YL]OXY}-1-BENZOFURAN-3-CARBOXAMIDE / PF-00337210


Mass: 461.510 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C26H27N3O5
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 337 / 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: 2.76 Å3/Da / Density % sol: 55.49 % / Description: NONE
Crystal growTemperature: 286 K / Method: vapor diffusion, hanging drop / pH: 7.5
Details: PROTEIN PRODUCTION, PROTEIN PURIFICATION, AND COCRYSTALLIZATION WERE PERFORMED AS PREVIOUSLY DESCRIBED (PUBLISHED INTERNATIONAL PATENT APPLICATION WO 2004/092217 HANGING DROP VAPOR DIFFUSION ...Details: PROTEIN PRODUCTION, PROTEIN PURIFICATION, AND COCRYSTALLIZATION WERE PERFORMED AS PREVIOUSLY DESCRIBED (PUBLISHED INTERNATIONAL PATENT APPLICATION WO 2004/092217 HANGING DROP VAPOR DIFFUSION AT 13 DEGREES C. 2 MICROLITERS OF A 7.7 MG/ML PROTEIN SOLUTION (IN 50 MM HEPES 7.5, 30 MM SODIUM CHLORIDE, 5 MM DTT, AND 5% DMSO) WAS MIXED WITH 2 MICROLITERS OF CRYSTALLIZATION SOLUTION (100 MM HEPES PH 7.5, 20% PEG 6K AND 5% MPD) AND SUSPENDED OVER 1 ML OF CRYSTALLIZATION SOLUTION PLUS 5 MICROLITERS BME.

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Data collection

DiffractionMean temperature: 89 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.2 / Wavelength: 1
DetectorType: ADSC CCD / Detector: CCD / Date: Aug 4, 2004
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.45→50 Å / Num. obs: 67226 / % possible obs: 95.8 % / Observed criterion σ(I): 1 / Redundancy: 4.4 % / Rmerge(I) obs: 0.06 / Net I/σ(I): 22
Reflection shellResolution: 1.45→1.5 Å / Redundancy: 2.3 % / Rmerge(I) obs: 0.48 / Mean I/σ(I) obs: 1.22 / % possible all: 68.2

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Processing

Software
NameVersionClassification
REFMAC5.2.0019refinement
HKL-2000data reduction
HKL-2000data scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 1VR2

1vr2


Resolution: 1.5→19.92 Å / Cor.coef. Fo:Fc: 0.954 / Cor.coef. Fo:Fc free: 0.946 / SU B: 1.359 / SU ML: 0.052 / Cross valid method: THROUGHOUT / ESU R: 0.079 / ESU R Free: 0.078 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS.
RfactorNum. reflection% reflectionSelection details
Rfree0.23808 3178 5.1 %RANDOM
Rwork0.21747 ---
obs0.21852 59334 98.83 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK
Displacement parametersBiso mean: 23.671 Å2
Baniso -1Baniso -2Baniso -3
1-0.16 Å20 Å2-0.63 Å2
2---0.41 Å20 Å2
3---0.16 Å2
Refinement stepCycle: LAST / Resolution: 1.5→19.92 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2338 0 34 337 2709
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0060.0222434
X-RAY DIFFRACTIONr_bond_other_d0.0020.0210
X-RAY DIFFRACTIONr_angle_refined_deg1.0911.9773298
X-RAY DIFFRACTIONr_angle_other_deg16.781317
X-RAY DIFFRACTIONr_dihedral_angle_1_deg4.9215294
X-RAY DIFFRACTIONr_dihedral_angle_2_deg32.43122.897107
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.85615402
X-RAY DIFFRACTIONr_dihedral_angle_4_deg16.031518
X-RAY DIFFRACTIONr_chiral_restr0.0740.2356
X-RAY DIFFRACTIONr_gen_planes_refined0.0030.021855
X-RAY DIFFRACTIONr_gen_planes_other0.0060.029
X-RAY DIFFRACTIONr_nbd_refined0.1710.21172
X-RAY DIFFRACTIONr_nbd_other0.2870.218
X-RAY DIFFRACTIONr_nbtor_refined0.3040.21665
X-RAY DIFFRACTIONr_nbtor_other0.2140.213
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.0920.2285
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.1370.234
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.1030.211
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it0.4491.51518
X-RAY DIFFRACTIONr_mcbond_other0.021.53
X-RAY DIFFRACTIONr_mcangle_it0.7722364
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it1.01731102
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it1.6364.5934
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: 1.5→1.539 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.309 203 -
Rwork0.306 4003 -
obs--90.69 %

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