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- PDB-2rl5: Crystal structure of the VEGFR2 kinase domain in complex with a 2... -

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Basic information

Entry
Database: PDB / ID: 2rl5
TitleCrystal structure of the VEGFR2 kinase domain in complex with a 2,3-dihydro-1,4-benzoxazine 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 / Phosphorylation / Polymorphism / Transmembrane / Tyrosine-protein kinase
Function / homology
Function and homology information


positive regulation of nitric oxide-cGMP mediated signal transduction / 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 ...positive regulation of nitric oxide-cGMP mediated signal transduction / 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 / mesenchymal cell proliferation / positive regulation of vasculogenesis / 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 / positive regulation of endothelial cell chemotaxis / anchoring junction / embryonic hemopoiesis / 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 stem cell proliferation / positive regulation of mitochondrial depolarization / growth factor binding / sorting endosome / regulation of MAPK cascade / semaphorin-plexin signaling pathway / positive regulation of macroautophagy / cellular response to vascular endothelial growth factor stimulus / positive regulation of focal adhesion assembly / cell fate commitment / positive regulation of blood vessel endothelial cell migration / Integrin cell surface interactions / vascular endothelial growth factor receptor signaling pathway / negative regulation of endothelial cell apoptotic process / vasculogenesis / peptidyl-tyrosine autophosphorylation / calcium ion homeostasis / coreceptor activity / ovarian follicle development / positive regulation of endothelial cell proliferation / transmembrane receptor protein tyrosine kinase activity / positive regulation of endothelial cell migration / cell surface receptor protein tyrosine kinase signaling pathway / 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 / transmembrane-ephrin receptor activity / GPI-linked 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 / positive regulation of angiogenesis / integrin binding / cell junction / cell migration / regulation of cell shape / positive regulation of protein phosphorylation / protein autophosphorylation / High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells / protein tyrosine kinase activity / angiogenesis / negative regulation of neuron apoptotic process / early endosome / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / receptor complex / positive regulation of ERK1 and ERK2 cascade / positive regulation of MAPK cascade / endosome / positive regulation of cell migration / cadherin binding / membrane raft / external side of plasma membrane / negative regulation of gene expression
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. / Tyrosine-protein kinase, active site / Immunoglobulin subtype / Immunoglobulin / Serine-threonine/tyrosine-protein kinase, catalytic domain / Protein tyrosine and serine/threonine kinase / Phosphorylase Kinase; domain 1 / Ig-like domain profile. / Immunoglobulin-like domain / Phosphorylase Kinase; domain 1 / Transferase(Phosphotransferase) domain 1 / Immunoglobulin-like domain superfamily / 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
Chem-2RL / Vascular endothelial growth factor receptor 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 2.65 Å
AuthorsWhittington, D.A. / Long, A.M. / Rose, P. / Zhao, H.
CitationJournal: J.Med.Chem. / Year: 2008
Title: Novel 2,3-dihydro-1,4-benzoxazines as potent and orally bioavailable inhibitors of tumor-driven angiogenesis.
Authors: La, D.S. / Belzile, J. / Bready, J.V. / Coxon, A. / Demelfi, T. / Doerr, N. / Estrada, J. / Flynn, J.C. / Flynn, S.R. / Graceffa, R.F. / Harriman, S.P. / Larrow, J.F. / Long, A.M. / Martin, ...Authors: La, D.S. / Belzile, J. / Bready, J.V. / Coxon, A. / Demelfi, T. / Doerr, N. / Estrada, J. / Flynn, J.C. / Flynn, S.R. / Graceffa, R.F. / Harriman, S.P. / Larrow, J.F. / Long, A.M. / Martin, M.W. / Morrison, M.J. / Patel, V.F. / Roveto, P.M. / Wang, L. / Weiss, M.M. / Whittington, D.A. / Teffera, Y. / Zhao, Z. / Polverino, A.J. / Harmange, J.C.
History
DepositionOct 18, 2007Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 8, 2008Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Jul 26, 2017Group: Source and taxonomy / Category: entity_src_gen
Revision 1.3Nov 13, 2019Group: Structure summary / Category: struct_keywords / Item: _struct_keywords.text
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
Revision 1.6Oct 16, 2024Group: Structure summary / Category: pdbx_entry_details / Item: _pdbx_entry_details.has_protein_modification

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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)36,7772
Polymers36,2851
Non-polymers4921
Water2,504139
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)66.760, 139.774, 57.550
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number18
Space group name H-MP21212

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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.: 1 / 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-2RL / N-(4-CHLOROPHENYL)-7-[(6,7-DIMETHOXYQUINOLIN-4-YL)OXY]-2,3-DIHYDRO-1,4-BENZOXAZINE-4-CARBOXAMIDE


Mass: 491.923 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C26H22ClN3O5
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 139 / Source method: isolated from a natural source / Formula: H2O
Has protein modificationN
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: 3.72 Å3/Da / Density % sol: 66.9 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 8.2
Details: PEG 4000, lithium sulfate, Tris, pH 8.2, VAPOR DIFFUSION, HANGING DROP, temperature 277K

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Data collection

DiffractionMean temperature: 97 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.2
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Jan 11, 2005
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthRelative weight: 1
ReflectionResolution: 2.65→30 Å / Num. all: 16297 / Num. obs: 16281 / % possible obs: 99.9 % / Observed criterion σ(I): -3 / Redundancy: 4.8 % / Biso Wilson estimate: 32.6 Å2 / Rmerge(I) obs: 0.115 / Χ2: 1.113 / Net I/σ(I): 13.7
Reflection shellResolution: 2.65→2.74 Å / Redundancy: 4.6 % / Rmerge(I) obs: 0.437 / Mean I/σ(I) obs: 3.4 / Num. unique all: 1598 / Χ2: 1.077 / % possible all: 99.6

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Processing

Software
NameVersionClassificationNB
SCALEPACKdata scaling
CNSrefinement
PDB_EXTRACT1.401data extraction
DENZOdata reduction
CNSphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 2.65→30 Å / Data cutoff high absF: 10000 / Data cutoff low absF: 0 / Cross valid method: THROUGHOUT / σ(F): 0 / Stereochemistry target values: Engh & Huber
RfactorNum. reflection% reflectionSelection details
Rfree0.233 1268 7.8 %random
Rwork0.199 ---
all-16269 --
obs-16246 99.9 %-
Displacement parameters
Baniso -1Baniso -2Baniso -3
1-1.201 Å20 Å20 Å2
2---4.031 Å20 Å2
3---2.83 Å2
Refine analyze
FreeObs
Luzzati coordinate error0.36 Å0.3 Å
Luzzati d res low-5 Å
Luzzati sigma a0.31 Å0.29 Å
Refinement stepCycle: LAST / Resolution: 2.65→30 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2370 0 35 139 2544
Refine LS restraints
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONc_bond_d0.006
X-RAY DIFFRACTIONc_angle_deg1.2
X-RAY DIFFRACTIONc_dihedral_angle_d21.1
X-RAY DIFFRACTIONc_improper_angle_d0.77

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