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

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Basic information

Entry
Database: PDB / ID: 6gqq
TitleCrystal structure of human KDR (VEGFR2) kinase domain in complex with AZD3229-analogue (compound 35)
ComponentsVascular endothelial growth factor receptor 2VEGF receptor
KeywordsSIGNALING PROTEIN / receptor tyrosine kinase / inhibitor / oncology / gastrointestinal stromal tumour / structure-based drug design
Function / homology
Function and homology information


blood vessel endothelial cell differentiation / cellular response to hydrogen sulfide / regulation of bone development / Signaling by membrane-tethered fusions of PDGFRA or PDGFRB / vascular endothelial growth factor binding / Neurophilin interactions with VEGF and VEGFR / endothelium development / vascular endothelial growth factor receptor-2 signaling pathway / VEGF binds to VEGFR leading to receptor dimerization / endocardium development ...blood vessel endothelial cell differentiation / cellular response to hydrogen sulfide / regulation of bone development / Signaling by membrane-tethered fusions of PDGFRA or PDGFRB / vascular endothelial growth factor binding / Neurophilin interactions with VEGF and VEGFR / endothelium development / vascular endothelial growth factor receptor-2 signaling pathway / VEGF binds to VEGFR leading to receptor dimerization / endocardium development / vascular wound healing / vascular endothelial growth factor receptor activity / regulation of hematopoietic progenitor cell differentiation / post-embryonic camera-type eye morphogenesis / endothelial cell differentiation / mesenchymal cell proliferation / positive regulation of vasculogenesis / lymph vessel development / positive regulation of BMP signaling pathway / surfactant homeostasis / cell migration involved in sprouting angiogenesis / anchoring junction / epithelial cell maturation / positive regulation of positive chemotaxis / embryonic hemopoiesis / vascular endothelial growth factor signaling pathway / positive regulation of endothelial cell chemotaxis / positive regulation of mesenchymal cell proliferation / positive regulation of mitochondrial depolarization / branching involved in blood vessel morphogenesis / positive regulation of cell migration involved in sprouting angiogenesis / positive regulation of mitochondrial fission / lung alveolus development / positive regulation of stem cell proliferation / positive regulation of nitric-oxide synthase biosynthetic process / sorting endosome / growth factor binding / positive regulation of focal adhesion assembly / regulation of MAPK cascade / semaphorin-plexin signaling pathway / positive regulation of macroautophagy / : / positive regulation of blood vessel endothelial cell migration / cellular response to vascular endothelial growth factor stimulus / cell fate commitment / calcium ion homeostasis / Integrin cell surface interactions / vasculogenesis / vascular endothelial growth factor receptor signaling pathway / coreceptor activity / negative regulation of endothelial cell apoptotic process / peptidyl-tyrosine autophosphorylation / ovarian follicle development / positive regulation of endothelial cell proliferation / transmembrane receptor protein tyrosine kinase activity / positive regulation of endothelial cell migration / VEGFR2 mediated cell proliferation / epithelial cell proliferation / stem cell proliferation / cell surface receptor protein tyrosine kinase signaling pathway / Hsp90 protein binding / receptor protein-tyrosine kinase / VEGFA-VEGFR2 Pathway / peptidyl-tyrosine phosphorylation / positive regulation of angiogenesis / cell migration / integrin binding / cell junction / regulation of cell shape / protein tyrosine kinase activity / angiogenesis / negative regulation of neuron apoptotic process / positive regulation of MAPK cascade / protein autophosphorylation / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / early endosome / positive regulation of ERK1 and ERK2 cascade / receptor complex / endosome / positive regulation of cell migration / cadherin binding / membrane raft / positive regulation of protein phosphorylation / external side of plasma membrane / negative regulation of gene expression / positive regulation of cell population proliferation / negative regulation of apoptotic process / 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 / Tyrosine-protein kinase, receptor class III, conserved site / Receptor tyrosine kinase class III signature. / Immunoglobulin domain / Immunoglobulin / Immunoglobulin domain / Immunoglobulin I-set ...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 / 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 / Protein tyrosine and serine/threonine kinase / Serine-threonine/tyrosine-protein kinase, catalytic domain / 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-F8B / Vascular endothelial growth factor receptor 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.52 Å
AuthorsSchimpl, M. / Hardy, C.J. / Ogg, D.J. / Overman, R.C. / Packer, M.J. / Kettle, J.G. / Anjum, R. / Barry, E. / Bhavsar, D. / Brown, C. ...Schimpl, M. / Hardy, C.J. / Ogg, D.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

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Assembly

Deposited unit
A: Vascular endothelial growth factor receptor 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)37,4382
Polymers36,9901
Non-polymers4481
Water4,342241
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 area15600 Å2
MethodPISA
Unit cell
Length a, b, c (Å)52.690, 56.540, 61.380
Angle α, β, γ (deg.)90.00, 110.24, 90.00
Int Tables number4
Space group name H-MP1211

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Components

#1: Protein Vascular endothelial growth factor receptor 2 / VEGF receptor / 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-F8B / ~{N}-[4-(6,7-dimethoxyquinazolin-4-yl)oxyphenyl]-2-(4-propan-2-yl-1,2,3-triazol-1-yl)ethanamide


Mass: 448.474 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C23H24N6O4 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 241 / 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: 2.32 Å3/Da / Density % sol: 46.96 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 7.2
Details: 5 % PEG 8000, 0.1 M PCTP (sodium propionate, sodium cacodylate trihydrate, bis-tris propane) pH 7.2

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I04-1 / Wavelength: 0.92819 Å
DetectorType: DECTRIS PILATUS 6M-F / Detector: PIXEL / Date: Apr 16, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.92819 Å / Relative weight: 1
ReflectionResolution: 1.516→57.585 Å / Num. obs: 49512 / % possible obs: 94.2 % / Redundancy: 3.1 % / Biso Wilson estimate: 24.04 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.035 / Net I/σ(I): 14.8
Reflection shellResolution: 1.516→1.521 Å / Redundancy: 2.4 % / Rmerge(I) obs: 0.341 / Mean I/σ(I) obs: 2 / Num. unique obs: 441 / CC1/2: 0.856 / % possible all: 86.3

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Processing

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

3wzd


Resolution: 1.52→57.58 Å / Cor.coef. Fo:Fc: 0.959 / Cor.coef. Fo:Fc free: 0.946 / Rfactor Rfree error: 0 / SU R Cruickshank DPI: 0.073 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.075 / SU Rfree Blow DPI: 0.075 / SU Rfree Cruickshank DPI: 0.074
RfactorNum. reflection% reflectionSelection details
Rfree0.204 2465 5.01 %RANDOM
Rwork0.177 ---
obs0.178 49157 94.2 %-
Displacement parametersBiso mean: 30.07 Å2
Baniso -1Baniso -2Baniso -3
1-2.5602 Å20 Å21.0392 Å2
2--1.5587 Å20 Å2
3----4.1189 Å2
Refine analyzeLuzzati coordinate error obs: 0.18 Å
Refinement stepCycle: LAST / Resolution: 1.52→57.58 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2446 0 33 241 2720
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.012564HARMONIC2
X-RAY DIFFRACTIONt_angle_deg0.93470HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d898SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes52HARMONIC2
X-RAY DIFFRACTIONt_gen_planes374HARMONIC5
X-RAY DIFFRACTIONt_it2564HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion3.42
X-RAY DIFFRACTIONt_other_torsion19.77
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion316SEMIHARMONIC5
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_contact2803SEMIHARMONIC4
LS refinement shellResolution: 1.52→1.56 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.209 175 5.21 %
Rwork0.214 3181 -
all0.214 3356 -
obs--87.77 %
Refinement TLS params.Method: refined / Origin x: 21.5136 Å / Origin y: -0.5025 Å / Origin z: 12.2711 Å
111213212223313233
T-0.207 Å20.0057 Å20.0163 Å2--0.2068 Å2-0.009 Å2---0.2099 Å2
L0.9793 °2-0.0254 °20.155 °2-0.7342 °2-0.1208 °2--0.7427 °2
S-0.0071 Å °-0.1699 Å °0.0018 Å °0.0812 Å °-0.0112 Å °0.0311 Å °-0.0081 Å °0.0751 Å °0.0183 Å °
Refinement TLS groupSelection details: { A|* }

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