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Yorodumi- PDB-6gqq: Crystal structure of human KDR (VEGFR2) kinase domain in complex ... -
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-Basic information
Entry | Database: PDB / ID: 6gqq | ||||||
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Title | Crystal structure of human KDR (VEGFR2) kinase domain in complex with AZD3229-analogue (compound 35) | ||||||
Components | Vascular endothelial growth factor receptor 2 | ||||||
Keywords | SIGNALING 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 / vascular endothelial growth factor receptor-2 signaling pathway / VEGF binds to VEGFR leading to receptor dimerization / endothelium development / 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 / vascular endothelial growth factor receptor-2 signaling pathway / VEGF binds to VEGFR leading to receptor dimerization / endothelium development / endocardium development / vascular wound healing / regulation of hematopoietic progenitor cell differentiation / vascular endothelial growth factor receptor activity / post-embryonic camera-type eye morphogenesis / endothelial cell differentiation / positive regulation of vasculogenesis / mesenchymal cell proliferation / lymph vessel development / 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 / branching involved in blood vessel morphogenesis / positive regulation of cell migration involved in sprouting angiogenesis / positive regulation of mitochondrial fission / positive regulation of mitochondrial depolarization / lung alveolus development / positive regulation of stem cell proliferation / positive regulation of nitric-oxide synthase biosynthetic process / growth factor binding / sorting endosome / 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 / vasculogenesis / Integrin cell surface interactions / 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 / cell surface receptor protein tyrosine kinase signaling pathway / positive regulation of endothelial cell migration / transmembrane receptor protein tyrosine kinase activity / VEGFR2 mediated cell proliferation / epithelial cell proliferation / stem cell proliferation / 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 / positive regulation of ERK1 and ERK2 cascade / 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 / negative regulation of apoptotic process / Golgi apparatus / endoplasmic reticulum / extracellular region / ATP binding / identical protein binding / nucleus / plasma membrane Similarity search - Function | ||||||
Biological species | Homo sapiens (human) | ||||||
Method | X-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.52 Å | ||||||
Authors | 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. ...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. | ||||||
Citation | Journal: 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 |
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-Structure visualization
Structure viewer | Molecule: MolmilJmol/JSmol |
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-Downloads & links
-Download
PDBx/mmCIF format | 6gqq.cif.gz | 143.4 KB | Display | PDBx/mmCIF format |
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PDB format | pdb6gqq.ent.gz | 109.5 KB | Display | PDB format |
PDBx/mmJSON format | 6gqq.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Summary document | 6gqq_validation.pdf.gz | 673.2 KB | Display | wwPDB validaton report |
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Full document | 6gqq_full_validation.pdf.gz | 673.8 KB | Display | |
Data in XML | 6gqq_validation.xml.gz | 15.1 KB | Display | |
Data in CIF | 6gqq_validation.cif.gz | 22.6 KB | Display | |
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/gq/6gqq ftp://data.pdbj.org/pub/pdb/validation_reports/gq/6gqq | HTTPS FTP |
-Related structure data
Related structure data | 6gqjC 6gqkC 6gqlC 6gqmC 6gqoC 6gqpC 3wzdS S: Starting model for refinement C: citing same article (ref.) |
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Similar structure data |
-Links
-Assembly
Deposited unit |
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1 |
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Unit cell |
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-Components
#1: Protein | 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 |
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#2: Chemical | ChemComp-F8B / ~{ |
#3: Water | ChemComp-HOH / |
-Experimental details
-Experiment
Experiment | Method: X-RAY DIFFRACTION / Number of used crystals: 1 |
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-Sample preparation
Crystal | Density Matthews: 2.32 Å3/Da / Density % sol: 46.96 % |
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Crystal grow | Temperature: 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 |
-Data collection
Diffraction | Mean temperature: 100 K |
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Diffraction source | Source: SYNCHROTRON / Site: Diamond / Beamline: I04-1 / Wavelength: 0.92819 Å |
Detector | Type: DECTRIS PILATUS 6M-F / Detector: PIXEL / Date: Apr 16, 2016 |
Radiation | Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray |
Radiation wavelength | Wavelength: 0.92819 Å / Relative weight: 1 |
Reflection | Resolution: 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 shell | Resolution: 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 |
-Processing
Software |
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Refinement | Method to determine structure: MOLECULAR REPLACEMENT Starting model: 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
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Displacement parameters | Biso mean: 30.07 Å2
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Refine analyze | Luzzati coordinate error obs: 0.18 Å | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Refinement step | Cycle: LAST / Resolution: 1.52→57.58 Å
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Refine LS restraints |
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LS refinement shell | Resolution: 1.52→1.56 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
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Refinement TLS params. | Method: refined / Origin x: 21.5136 Å / Origin y: -0.5025 Å / Origin z: 12.2711 Å
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Refinement TLS group | Selection details: { A|* } |