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- PDB-1y6b: Crystal structure of VEGFR2 in complex with a 2-anilino-5-aryl-ox... -

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Basic information

Entry
Database: PDB / ID: 1y6b
TitleCrystal structure of VEGFR2 in complex with a 2-anilino-5-aryl-oxazole inhibitor
ComponentsVascular endothelial growth factor receptor 2
KeywordsTRANSFERASE
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-AAX / Vascular endothelial growth factor receptor 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.1 Å
AuthorsHarris, P.A. / Cheung, M. / Hunter, R.N. / Brown, M.L. / Veal, J.M. / Nolte, R.T. / Wang, L. / Liu, W. / Crosby, R.M. / Johnson, J.H. ...Harris, P.A. / Cheung, M. / Hunter, R.N. / Brown, M.L. / Veal, J.M. / Nolte, R.T. / Wang, L. / Liu, W. / Crosby, R.M. / Johnson, J.H. / Epperly, A.H. / Kumar, R. / Luttrell, D.K. / Stafford, J.A.
CitationJournal: J.Med.Chem. / Year: 2005
Title: Discovery and evaluation of 2-anilino-5-aryloxazoles as a novel class of VEGFR2 kinase inhibitors.
Authors: Harris, P.A. / Cheung, M. / Hunter, R.N. / Brown, M.L. / Veal, J.M. / Nolte, R.T. / Wang, L. / Liu, W. / Crosby, R.M. / Johnson, J.H. / Epperly, A.H. / Kumar, R. / Luttrell, D.K. / Stafford, J.A.
History
DepositionDec 5, 2004Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 7, 2005Provider: repository / Type: Initial release
Revision 1.1Apr 30, 2008Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Advisory / Version format compliance
Revision 1.3Oct 11, 2017Group: Refinement description / Category: software / Item: _software.classification / _software.name
Revision 1.4Feb 14, 2024Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _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)42,1532
Polymers41,6771
Non-polymers4771
Water2,720151
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)37.544, 94.333, 96.767
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


Mass: 41676.695 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: KDR, FLK1 / Production host: Escherichia coli (E. coli) / References: UniProt: P35968, EC: 2.7.1.112
#2: Chemical ChemComp-AAX / N-(CYCLOPROPYLMETHYL)-4-(METHYLOXY)-3-({5-[3-(3-PYRIDINYL)PHENYL]-1,3-OXAZOL-2-YL}AMINO)BENZENESULFONAMIDE


Mass: 476.547 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C25H24N4O4S
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 151 / Source method: isolated from a natural source / Formula: H2O

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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: 2.06 Å3/Da / Density % sol: 40.17 %

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Data collection

Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.1→20 Å / Num. all: 20768 / Num. obs: 20768 / % possible obs: 99.5 % / Observed criterion σ(F): 0 / Observed criterion σ(I): -3 / Redundancy: 6.79 % / Biso Wilson estimate: 36 Å2 / Rmerge(I) obs: 0.045 / Net I/σ(I): 42.9
Reflection shellResolution: 2.1→2.17 Å / Rmerge(I) obs: 0.355 / Mean I/σ(I) obs: 5.46 / % possible all: 99.1

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Processing

Software
NameVersionClassification
REFMAC5.2.0005refinement
MAR345data collection
SCALEPACKdata scaling
AMoREphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.1→16.6 Å / Cor.coef. Fo:Fc: 0.955 / Cor.coef. Fo:Fc free: 0.935 / SU B: 8.89 / SU ML: 0.124 / TLS residual ADP flag: LIKELY RESIDUAL / Cross valid method: THROUGHOUT / ESU R: 0.19 / ESU R Free: 0.171 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.23588 675 3.3 %RANDOM
Rwork0.19248 ---
obs0.19385 19994 99.67 %-
all-20795 --
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 35.596 Å2
Baniso -1Baniso -2Baniso -3
1-1.65 Å20 Å20 Å2
2---0.02 Å20 Å2
3----1.63 Å2
Refinement stepCycle: LAST / Resolution: 2.1→16.6 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2135 0 34 151 2320
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0160.0222224
X-RAY DIFFRACTIONr_bond_other_d0.0020.022048
X-RAY DIFFRACTIONr_angle_refined_deg1.5391.9823003
X-RAY DIFFRACTIONr_angle_other_deg0.98134751
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.625261
X-RAY DIFFRACTIONr_dihedral_angle_2_deg32.122.70896
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.05515388
X-RAY DIFFRACTIONr_dihedral_angle_4_deg23.2641517
X-RAY DIFFRACTIONr_chiral_restr0.0960.2326
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.022398
X-RAY DIFFRACTIONr_gen_planes_other0.0070.02475
X-RAY DIFFRACTIONr_nbd_refined0.2160.2427
X-RAY DIFFRACTIONr_nbd_other0.1840.21935
X-RAY DIFFRACTIONr_nbtor_refined0.1830.21045
X-RAY DIFFRACTIONr_nbtor_other0.0840.21195
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1920.2114
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.0370.23
X-RAY DIFFRACTIONr_symmetry_vdw_other0.1610.230
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.4990.21
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it1.3621.51709
X-RAY DIFFRACTIONr_mcbond_other0.2261.5537
X-RAY DIFFRACTIONr_mcangle_it1.54522132
X-RAY DIFFRACTIONr_scbond_it2.25631071
X-RAY DIFFRACTIONr_scangle_it3.2134.5868
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.1→2.154 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.338 39 -
Rwork0.217 1429 -
obs--98.86 %
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)
11.61410.23750.05162.16840.67252.82380.00030.07060.0597-0.0606-0.01930.1841-0.1453-0.090.019-0.07280.00540.0011-0.0119-0.01-0.06582.11834.2236.18
20.94180.59070.3752.54422.01363.0375-0.0587-0.01630.02850.2259-0.01830.06240.0971-0.04580.077-0.00080.0099-0.0039-0.0514-0.0331-0.11747.68441.43132.389
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
1X-RAY DIFFRACTION1AA817 - 92014 - 117
2X-RAY DIFFRACTION2AA921 - 1166118 - 363

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