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- PDB-6gqo: Crystal structure of human KDR (VEGFR2) kinase domain in complex ... -

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Basic information

Entry
Database: PDB / ID: 6gqo
TitleCrystal structure of human KDR (VEGFR2) kinase domain in complex with AZD3229-analogue (compound 18)
ComponentsVascular endothelial growth factor receptor 2
KeywordsSIGNALING PROTEIN / receptor tyrosine kinase / inhibitor / oncology / gastrointestinal stromal tumour / structure-based drug design
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 / 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 ...cellular response to hydrogen sulfide / blood vessel endothelial cell differentiation / regulation of bone development / Signaling by membrane-tethered fusions of PDGFRA or PDGFRB / 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 / vascular endothelial growth factor receptor activity / regulation of hematopoietic progenitor cell differentiation / post-embryonic camera-type eye morphogenesis / 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 / epithelial cell maturation / anchoring junction / positive regulation of positive chemotaxis / embryonic hemopoiesis / vascular endothelial growth factor signaling pathway / positive regulation of mesenchymal cell proliferation / positive regulation of endothelial cell chemotaxis / 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 / lung alveolus development / positive regulation of stem cell proliferation / : / sorting endosome / growth factor binding / positive regulation of focal adhesion assembly / positive regulation of macroautophagy / regulation of MAPK cascade / semaphorin-plexin signaling pathway / positive regulation of blood vessel endothelial cell migration / cellular response to vascular endothelial growth factor stimulus / cell fate commitment / vasculogenesis / Integrin cell surface interactions / vascular endothelial growth factor receptor signaling pathway / negative regulation of endothelial cell apoptotic process / coreceptor activity / calcium ion homeostasis / peptidyl-tyrosine autophosphorylation / ovarian follicle development / cell surface receptor protein tyrosine kinase signaling pathway / positive regulation of endothelial cell proliferation / transmembrane receptor protein tyrosine kinase activity / positive regulation of endothelial cell migration / VEGFR2 mediated cell proliferation / stem cell proliferation / epithelial 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 / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / early endosome / 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. / Immunoglobulin subtype / Immunoglobulin / Tyrosine-protein kinase, active site / 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-F82 / Vascular endothelial growth factor receptor 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.87 Å
AuthorsOgg, D.J. / Schimpl, M. / Hardy, C.J. / Overman, R.C. / Packer, M.J. / Kettle, J.G. / Anjum, R. / Barry, E. / Bhavsar, D. / Brown, C. ...Ogg, D.J. / Schimpl, M. / Hardy, C.J. / Overman, R.C. / Packer, M.J. / Kettle, J.G. / Anjum, R. / Barry, E. / Bhavsar, D. / Brown, C. / Campbell, A. / Goldberg, K. / Grondine, M. / Guichard, S. / Hunt, T. / Jones, O. / Li, X. / Moleva, O. / Pearson, S. / Shao, W. / Smith, A. / Smith, J. / Stead, D. / Stokes, S. / Tucker, M. / Ye, Y.
CitationJournal: J. Med. Chem. / Year: 2018
Title: Discovery of N-(4-{[5-Fluoro-7-(2-methoxyethoxy)quinazolin-4-yl]amino}phenyl)-2-[4-(propan-2-yl)-1 H-1,2,3-triazol-1-yl]acetamide (AZD3229), a Potent Pan-KIT Mutant Inhibitor for the Treatment ...Title: Discovery of N-(4-{[5-Fluoro-7-(2-methoxyethoxy)quinazolin-4-yl]amino}phenyl)-2-[4-(propan-2-yl)-1 H-1,2,3-triazol-1-yl]acetamide (AZD3229), a Potent Pan-KIT Mutant Inhibitor for the Treatment of Gastrointestinal Stromal Tumors.
Authors: Kettle, J.G. / Anjum, R. / Barry, E. / Bhavsar, D. / Brown, C. / Boyd, S. / Campbell, A. / Goldberg, K. / Grondine, M. / Guichard, S. / Hardy, C.J. / Hunt, T. / Jones, R.D.O. / Li, X. / ...Authors: Kettle, J.G. / Anjum, R. / Barry, E. / Bhavsar, D. / Brown, C. / Boyd, S. / Campbell, A. / Goldberg, K. / Grondine, M. / Guichard, S. / Hardy, C.J. / Hunt, T. / Jones, R.D.O. / Li, X. / Moleva, O. / Ogg, D. / Overman, R.C. / Packer, M.J. / Pearson, S. / Schimpl, M. / Shao, W. / Smith, A. / Smith, J.M. / Stead, D. / Stokes, S. / Tucker, M. / Ye, Y.
History
DepositionJun 7, 2018Deposition site: PDBE / Processing site: PDBE
Revision 1.0Sep 19, 2018Provider: repository / Type: Initial release
Revision 1.1Oct 3, 2018Group: Data collection / Database references / Category: citation / citation_author
Item: _citation.title / _citation_author.identifier_ORCID / _citation_author.name
Revision 1.2Oct 31, 2018Group: Data collection / Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.3Jan 17, 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

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)37,4672
Polymers36,9901
Non-polymers4781
Water2,306128
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 area15530 Å2
MethodPISA
Unit cell
Length a, b, c (Å)52.104, 56.457, 60.714
Angle α, β, γ (deg.)90.00, 110.45, 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 / 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
Source method: isolated from a genetically manipulated source
Details: Human KDR kinase domain D807-D1171 with an internal deletion of T940-E990, replaced by a single valine
Source: (gene. exp.) Homo sapiens (human) / Gene: KDR, FLK1, VEGFR2 / Cell line (production host): Sf21 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P35968, receptor protein-tyrosine kinase
#2: Chemical ChemComp-F82 / 2-[4-(6,7-dimethoxyquinazolin-4-yl)oxy-2-methoxy-phenyl]-~{N}-(1-propan-2-ylpyrazol-4-yl)ethanamide


Mass: 477.512 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C25H27N5O5 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 128 / 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: 2.38 Å3/Da / Density % sol: 48.36 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 8.5 / Details: 8 % PEG 8000, 0.1 M Tris pH 8.5

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I02 / Wavelength: 0.97949 Å
DetectorType: DECTRIS PILATUS 6M-F / Detector: PIXEL / Date: Sep 26, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97949 Å / Relative weight: 1
ReflectionResolution: 1.87→56.46 Å / Num. obs: 27358 / % possible obs: 99.3 % / Redundancy: 6.4 % / Biso Wilson estimate: 36.4 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.048 / Net I/σ(I): 17.1
Reflection shellResolution: 1.87→1.97 Å / Redundancy: 5 % / Rmerge(I) obs: 0.545 / Num. unique obs: 3860 / CC1/2: 0.822 / % possible all: 96.4

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Processing

Software
NameVersionClassification
BUSTER2.11.6refinement
xia2data reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3WZD

3wzd


Resolution: 1.87→48.82 Å / Cor.coef. Fo:Fc: 0.958 / Cor.coef. Fo:Fc free: 0.946 / Rfactor Rfree error: 0 / SU R Cruickshank DPI: 0.128 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.127 / SU Rfree Blow DPI: 0.119 / SU Rfree Cruickshank DPI: 0.12
RfactorNum. reflection% reflectionSelection details
Rfree0.207 1403 5.15 %RANDOM
Rwork0.172 ---
obs0.174 27268 99.3 %-
Displacement parametersBiso mean: 47.98 Å2
Baniso -1Baniso -2Baniso -3
1-5.0821 Å20 Å24.0083 Å2
2--0.0948 Å20 Å2
3----5.1769 Å2
Refine analyzeLuzzati coordinate error obs: 0.21 Å
Refinement stepCycle: 1 / Resolution: 1.87→48.82 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2460 0 35 128 2623
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.012586HARMONIC2
X-RAY DIFFRACTIONt_angle_deg0.973504HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d906SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes54HARMONIC2
X-RAY DIFFRACTIONt_gen_planes377HARMONIC5
X-RAY DIFFRACTIONt_it2586HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion3.21
X-RAY DIFFRACTIONt_other_torsion17.52
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion321SEMIHARMONIC5
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_contact3026SEMIHARMONIC4
LS refinement shellResolution: 1.87→1.94 Å / Rfactor Rfree error: 0 / Total num. of bins used: 14
RfactorNum. reflection% reflection
Rfree0.229 124 4.55 %
Rwork0.215 2602 -
all0.216 2726 -
obs--95.01 %
Refinement TLS params.Method: refined / Origin x: 21.5136 Å / Origin y: -0.5025 Å / Origin z: 12.2711 Å
111213212223313233
T-0.0899 Å2-0.0023 Å2-0.0032 Å2--0.0798 Å2-0.0005 Å2---0.0727 Å2
L2.2077 °2-0.1509 °20.3958 °2-1.8678 °2-0.3842 °2--1.3769 °2
S0.0087 Å °-0.3103 Å °-0.0112 Å °0.18 Å °-0.0425 Å °-0.0108 Å °-0.029 Å °0.2133 Å °0.0338 Å °
Refinement TLS groupSelection details: { A|* }

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