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- PDB-2qu6: Crystal structure of the VEGFR2 kinase domain in complex with a b... -

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Basic information

Entry
Database: PDB / ID: 2qu6
TitleCrystal structure of the VEGFR2 kinase domain in complex with a benzoxazole inhibitor
ComponentsVascular endothelial growth factor receptor 2
KeywordsTRANSFERASE / receptor tyrosine kinase / KDR / 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 / regulation of bone development / cellular response to hydrogen sulfide / 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 / regulation of bone development / cellular response to hydrogen sulfide / 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 / vascular endothelial growth factor receptor activity / endothelial cell differentiation / regulation of hematopoietic progenitor cell differentiation / post-embryonic camera-type eye morphogenesis / lymph vessel development / mesenchymal cell proliferation / positive regulation of vasculogenesis / 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 / positive regulation of cell migration involved in sprouting angiogenesis / embryonic hemopoiesis / positive regulation of mesenchymal cell proliferation / vascular endothelial growth factor signaling pathway / growth factor binding / lung alveolus development / positive regulation of mitochondrial fission / branching involved in blood vessel morphogenesis / positive regulation of mitochondrial depolarization / positive regulation of stem cell proliferation / sorting endosome / semaphorin-plexin signaling pathway / regulation of MAPK cascade / positive regulation of macroautophagy / cellular response to vascular endothelial growth factor stimulus / cell fate commitment / positive regulation of focal adhesion assembly / 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 / 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 / peptidyl-tyrosine phosphorylation / VEGFR2 mediated cell proliferation / epithelial cell proliferation / stem cell proliferation / Hsp90 protein binding / receptor protein-tyrosine kinase / VEGFA-VEGFR2 Pathway / integrin binding / positive regulation of protein phosphorylation / positive regulation of angiogenesis / cell junction / cell migration / regulation of cell shape / protein autophosphorylation / protein tyrosine kinase activity / High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells / angiogenesis / negative regulation of neuron apoptotic process / early endosome / positive regulation of ERK1 and ERK2 cascade / receptor complex / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / endosome / positive regulation of MAPK cascade / positive regulation of cell migration / cadherin binding / membrane raft / negative regulation of gene expression / external side of plasma membrane / positive regulation of cell population proliferation / endoplasmic reticulum / Golgi apparatus / 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. ...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 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); 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-857 / Vascular endothelial growth factor receptor 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.1 Å
AuthorsWhittington, D.A. / Kim, J.L. / Long, A.M. / Rose, P. / Gu, Y. / Zhao, H.
CitationJournal: J.Med.Chem. / Year: 2007
Title: Design, Synthesis, and Evaluation of Orally Active Benzimidazoles and Benzoxazoles as Vascular Endothelial Growth Factor-2 Receptor Tyrosine Kinase Inhibitors.
Authors: Potashman, M.H. / Bready, J. / Coxon, A. / Demelfi, T.M. / Dipietro, L. / Doerr, N. / Elbaum, D. / Estrada, J. / Gallant, P. / Germain, J. / Gu, Y. / Harmange, J.C. / Kaufman, S.A. / ...Authors: Potashman, M.H. / Bready, J. / Coxon, A. / Demelfi, T.M. / Dipietro, L. / Doerr, N. / Elbaum, D. / Estrada, J. / Gallant, P. / Germain, J. / Gu, Y. / Harmange, J.C. / Kaufman, S.A. / Kendall, R. / Kim, J.L. / Kumar, G.N. / Long, A.M. / Neervannan, S. / Patel, V.F. / Polverino, A. / Rose, P. / Plas, S.V. / Whittington, D. / Zanon, R. / Zhao, H.
History
DepositionAug 3, 2007Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 25, 2007Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Aug 2, 2017Group: Source and taxonomy / Category: entity_src_gen
Revision 1.3Oct 20, 2021Group: Database references / Category: database_2 / struct_ref_seq_dif
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ref_seq_dif.details
Revision 1.4Feb 21, 2024Group: Data collection / Category: chem_comp_atom / chem_comp_bond
Revision 1.5Oct 16, 2024Group: Structure summary / Category: pdbx_entry_details
Remark 999Sequence THIS IS A DELETION MUTANT (RESIDUES 940-989) OF UNIPROT ENTRY P35968.

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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)73,6815
Polymers72,5692
Non-polymers1,1123
Water4,179232
1
A: Vascular endothelial growth factor receptor 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,8893
Polymers36,2851
Non-polymers6042
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)36,7932
Polymers36,2851
Non-polymers5081
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)55.37, 67.37, 89.62
Angle α, β, γ (deg.)90.00, 92.98, 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: kinase domain / 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-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: SO4
#3: Chemical ChemComp-857 / 4-({2-[(4-chloro-3-{[(2S)-1-methylpyrrolidin-2-yl]methoxy}phenyl)amino]-1,3-benzoxazol-5-yl}oxy)-N-methylpyridine-2-carboxamide


Mass: 507.969 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C26H26ClN5O4
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 232 / Source method: isolated from a natural source / Formula: H2O
Has protein modificationN

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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: 2.31 Å3/Da / Density % sol: 46.76 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 8
Details: PEG 5000 MME, ammonium sulfate, sodium chloride, HEPES, isopropanol, beta-mercaptoethanol, pH 8.0, VAPOR DIFFUSION, HANGING DROP, temperature 277K

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Data collection

Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.2
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthRelative weight: 1
ReflectionResolution: 2→30 Å / Num. obs: 44127 / % possible obs: 98.8 % / Observed criterion σ(I): -3 / Redundancy: 3.3 % / Rmerge(I) obs: 0.053
Reflection shellResolution: 2→2.03 Å / Rmerge(I) obs: 0.418 / Mean I/σ(I) obs: 2.3 / % possible all: 93.1

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Processing

Software
NameVersionClassificationNB
CNSrefinement
PDB_EXTRACT1.401data extraction
DENZOdata reduction
SCALEPACKdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.1→30 Å / Data cutoff high absF: 10000 / Data cutoff low absF: 0 / σ(F): 0 / Stereochemistry target values: Engh & Huber
RfactorNum. reflection% reflection
Rfree0.272 1487 3.9 %
Rwork0.242 --
all-38644 -
obs-36940 95.6 %
Displacement parameters
Baniso -1Baniso -2Baniso -3
1-7.564 Å20 Å2-1.164 Å2
2--8.003 Å20 Å2
3----15.567 Å2
Refine analyze
FreeObs
Luzzati sigma a0.3 Å0.24 Å
Refinement stepCycle: LAST / Resolution: 2.1→30 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4389 0 77 232 4698
Refine LS restraints
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONc_bond_d0.009
X-RAY DIFFRACTIONc_angle_deg1.52

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