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- PDB-6xvk: Crystal structure of the KDR (VEGFR2) kinase domain in complex wi... -

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Basic information

Entry
Database: PDB / ID: 6xvk
TitleCrystal structure of the KDR (VEGFR2) kinase domain in complex with a type-II inhibitor bearing an acrylamide
ComponentsVascular endothelial growth factor receptor 2
KeywordsSIGNALING PROTEIN / type II kinase inhibitor / structure-based drug design
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 / endothelial cell differentiation / regulation of hematopoietic progenitor cell differentiation / vascular endothelial growth factor receptor activity / 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 / positive regulation of cell migration involved in sprouting angiogenesis / anchoring junction / 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 / 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 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-O3E / Vascular endothelial growth factor receptor 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.99 Å
AuthorsSchimpl, M. / McAuley, K. / Hoyt, E.A. / Thomas, M. / Bodnarchuk, M.S. / Lewis, H.J. / Barratt, D. / Deery, M.J. / Ogg, D.J. / Bernardes, G.J.L. ...Schimpl, M. / McAuley, K. / Hoyt, E.A. / Thomas, M. / Bodnarchuk, M.S. / Lewis, H.J. / Barratt, D. / Deery, M.J. / Ogg, D.J. / Bernardes, G.J.L. / Ward, R.A. / Kettle, J.G. / Waring, M.J.
CitationJournal: J.Am.Chem.Soc. / Year: 2020
Title: Alkynyl Benzoxazines and Dihydroquinazolines as Cysteine Targeting Covalent Warheads and Their Application in Identification of Selective Irreversible Kinase Inhibitors.
Authors: McAulay, K. / Hoyt, E.A. / Thomas, M. / Schimpl, M. / Bodnarchuk, M.S. / Lewis, H.J. / Barratt, D. / Bhavsar, D. / Robinson, D.M. / Deery, M.J. / Ogg, D.J. / Bernardes, G.J.L. / Ward, R.A. / ...Authors: McAulay, K. / Hoyt, E.A. / Thomas, M. / Schimpl, M. / Bodnarchuk, M.S. / Lewis, H.J. / Barratt, D. / Bhavsar, D. / Robinson, D.M. / Deery, M.J. / Ogg, D.J. / Bernardes, G.J.L. / Ward, R.A. / Waring, M.J. / Kettle, J.G.
History
DepositionJan 22, 2020Deposition site: PDBE / Processing site: PDBE
Revision 1.0May 27, 2020Provider: repository / Type: Initial release
Revision 1.1Jun 17, 2020Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.name
Revision 1.2May 1, 2024Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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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)37,5262
Polymers36,9901
Non-polymers5371
Water59433
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area14950 Å2
MethodPISA
Unit cell
Length a, b, c (Å)51.550, 57.010, 59.890
Angle α, β, γ (deg.)90.000, 109.730, 90.000
Int Tables number4
Space group name H-MP1211

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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


Mass: 36989.609 Da / Num. of mol.: 1 / Fragment: protein kinase domain (807-1171 del[940-989]) / Mutation: E990V
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: KDR, FLK1, VEGFR2 / Plasmid: pFastBac1 / Cell line (production host): Sf21 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P35968, receptor protein-tyrosine kinase
#2: Chemical ChemComp-O3E / ~{N}-(4,4-dimethyl-2-prop-1-ynyl-3,1-benzoxazin-6-yl)-2-[3-methoxy-5-(7-methoxyquinolin-4-yl)oxy-pyridin-2-yl]ethanamide


Mass: 536.578 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C31H28N4O5 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 33 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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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: 2.24 Å3/Da / Density % sol: 45.08 % / Mosaicity: 0.34 °
Crystal growTemperature: 293 K / Method: vapor diffusion / pH: 6.5 / Details: 11 % PEG8000, 0.1 M PCTP buffer pH 6.5

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SOLEIL / Beamline: PROXIMA 2 / Wavelength: 0.9801 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: May 30, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9801 Å / Relative weight: 1
ReflectionResolution: 1.98→48.52 Å / Num. obs: 22301 / % possible obs: 98.1 % / Redundancy: 3.4 % / Biso Wilson estimate: 55.34 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.035 / Rpim(I) all: 0.023 / Rrim(I) all: 0.042 / Net I/σ(I): 13.5 / Num. measured all: 75115 / Scaling rejects: 1
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. measured allNum. unique obsCC1/2Rpim(I) allRrim(I) allNet I/σ(I) obs% possible all
1.98-2.043.21.285447813930.3950.8311.5360.784.6
8.88-48.523.10.0158552740.9990.010.01844.398.2

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassificationNB
XDSdata reduction
Aimless0.7.4data scaling
AMoREphasing
BUSTERrefinement
PDB_EXTRACT3.25data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: internal model

Resolution: 1.99→48.52 Å / Cor.coef. Fo:Fc: 0.951 / Cor.coef. Fo:Fc free: 0.93 / SU R Cruickshank DPI: 0.183 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.177 / SU Rfree Blow DPI: 0.157 / SU Rfree Cruickshank DPI: 0.162
RfactorNum. reflection% reflectionSelection details
Rfree0.244 1115 5 %RANDOM
Rwork0.206 ---
obs0.208 22292 98 %-
Displacement parametersBiso max: 186.92 Å2 / Biso mean: 75.99 Å2 / Biso min: 36.99 Å2
Baniso -1Baniso -2Baniso -3
1--0.6828 Å20 Å26.3129 Å2
2--0.6206 Å20 Å2
3---0.0622 Å2
Refine analyzeLuzzati coordinate error obs: 0.31 Å
Refinement stepCycle: final / Resolution: 1.99→48.52 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2390 0 40 33 2463
Biso mean--47.52 59.68 -
Num. residues----298
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d875SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes411HARMONIC5
X-RAY DIFFRACTIONt_it2494HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion307SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact2847SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d2494HARMONIC20.009
X-RAY DIFFRACTIONt_angle_deg3374HARMONIC20.99
X-RAY DIFFRACTIONt_omega_torsion2.9
X-RAY DIFFRACTIONt_other_torsion19.25
LS refinement shellResolution: 1.99→2.01 Å / Rfactor Rfree error: 0 / Total num. of bins used: 50
RfactorNum. reflection% reflection
Rfree0.1882 22 4.93 %
Rwork0.2463 424 -
all0.2435 446 -
obs--65.54 %
Refinement TLS params.Method: refined / Origin x: -5.7405 Å / Origin y: -0.0332 Å / Origin z: 15.6195 Å
111213212223313233
T-0.221 Å20.0301 Å2-0.004 Å2--0.1953 Å2-0.0128 Å2---0.2593 Å2
L2.9145 °20.3097 °22.2612 °2-3.454 °22.144 °2--6.4769 °2
S0.0692 Å °-0.0681 Å °-0.1256 Å °-0.092 Å °-0.2419 Å °-0.0242 Å °-0.1655 Å °-0.6026 Å °0.1727 Å °
Refinement TLS groupSelection details: { A|* }

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