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Yorodumi- PDB-6gqj: Crystal structure of human c-KIT kinase domain in complex with AZ... -
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-Basic information
Entry | Database: PDB / ID: 6gqj | ||||||
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Title | Crystal structure of human c-KIT kinase domain in complex with AZD3229-analogue (compound 18) | ||||||
Components | Mast/stem cell growth factor receptor Kit | ||||||
Keywords | SIGNALING PROTEIN / receptor tyrosine kinase / inhibitor / oncology / gastrointestinal stromal tumour / structure-based drug design | ||||||
Function / homology | Function and homology information Dasatinib-resistant KIT mutants / Imatinib-resistant KIT mutants / KIT mutants bind TKIs / Masitinib-resistant KIT mutants / Nilotinib-resistant KIT mutants / Regorafenib-resistant KIT mutants / Signaling by kinase domain mutants of KIT / Sunitinib-resistant KIT mutants / Signaling by juxtamembrane domain KIT mutants / Sorafenib-resistant KIT mutants ...Dasatinib-resistant KIT mutants / Imatinib-resistant KIT mutants / KIT mutants bind TKIs / Masitinib-resistant KIT mutants / Nilotinib-resistant KIT mutants / Regorafenib-resistant KIT mutants / Signaling by kinase domain mutants of KIT / Sunitinib-resistant KIT mutants / Signaling by juxtamembrane domain KIT mutants / Sorafenib-resistant KIT mutants / Signaling by extracellular domain mutants of KIT / stem cell factor receptor activity / hematopoietic stem cell migration / melanocyte adhesion / positive regulation of pyloric antrum smooth muscle contraction / positive regulation of colon smooth muscle contraction / erythropoietin-mediated signaling pathway / positive regulation of vascular associated smooth muscle cell differentiation / melanocyte migration / positive regulation of dendritic cell cytokine production / Kit signaling pathway / regulation of bile acid metabolic process / positive regulation of small intestine smooth muscle contraction / mast cell differentiation / positive regulation of mast cell proliferation / mast cell chemotaxis / Fc receptor signaling pathway / glycosphingolipid metabolic process / mast cell proliferation / positive regulation of long-term neuronal synaptic plasticity / detection of mechanical stimulus involved in sensory perception of sound / positive regulation of pseudopodium assembly / immature B cell differentiation / melanocyte differentiation / positive regulation of mast cell cytokine production / lymphoid progenitor cell differentiation / germ cell migration / myeloid progenitor cell differentiation / digestive tract development / negative regulation of programmed cell death / embryonic hemopoiesis / lamellipodium assembly / tongue development / megakaryocyte development / Regulation of KIT signaling / pigmentation / stem cell population maintenance / mast cell degranulation / positive regulation of Notch signaling pathway / cytokine binding / negative regulation of reproductive process / negative regulation of developmental process / growth factor binding / somatic stem cell population maintenance / hemopoiesis / T cell differentiation / spermatid development / ectopic germ cell programmed cell death / hematopoietic progenitor cell differentiation / : / response to cadmium ion / ovarian follicle development / positive regulation of tyrosine phosphorylation of STAT protein / TFAP2 (AP-2) family regulates transcription of growth factors and their receptors / transmembrane receptor protein tyrosine kinase activity / SH2 domain binding / B cell differentiation / erythrocyte differentiation / cell chemotaxis / acrosomal vesicle / Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants / epithelial cell proliferation / stem cell differentiation / positive regulation of receptor signaling pathway via JAK-STAT / visual learning / Signaling by SCF-KIT / receptor protein-tyrosine kinase / cytoplasmic side of plasma membrane / fibrillar center / cytokine-mediated signaling pathway / positive regulation of DNA-binding transcription factor activity / Constitutive Signaling by Aberrant PI3K in Cancer / male gonad development / cell-cell junction / PIP3 activates AKT signaling / regulation of cell population proliferation / regulation of cell shape / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / actin cytoskeleton organization / RAF/MAP kinase cascade / spermatogenesis / protein tyrosine kinase activity / protease binding / positive regulation of MAPK cascade / protein autophosphorylation / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / receptor complex / intracellular signal transduction / positive regulation of cell migration / inflammatory response Similarity search - Function | ||||||
Biological species | Homo sapiens (human) | ||||||
Method | X-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.33 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 | 6gqj.cif.gz | 256.8 KB | Display | PDBx/mmCIF format |
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PDB format | pdb6gqj.ent.gz | 207.5 KB | Display | PDB format |
PDBx/mmJSON format | 6gqj.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Summary document | 6gqj_validation.pdf.gz | 901.9 KB | Display | wwPDB validaton report |
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Full document | 6gqj_full_validation.pdf.gz | 905.3 KB | Display | |
Data in XML | 6gqj_validation.xml.gz | 24.9 KB | Display | |
Data in CIF | 6gqj_validation.cif.gz | 34.9 KB | Display | |
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/gq/6gqj ftp://data.pdbj.org/pub/pdb/validation_reports/gq/6gqj | HTTPS FTP |
-Related structure data
Related structure data | 6gqkC 6gqlC 6gqmC 6gqoC 6gqpC 6gqqC 4hvsS 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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2 |
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Unit cell |
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-Components
#1: Protein | Mass: 37194.430 Da / Num. of mol.: 2 Mutation: I563S, V569S, Y609Q, L631S, M651E, I662H, D768H, R804N, V825D, C844S, L890S, H894Y, L912D, L923D Source method: isolated from a genetically manipulated source Details: Human c-KIT kinase domain (P551-H934) bearing surface mutations to optimise protein expression (I563S, V569S, Y609Q, L631S, M651E, I662H, D768H, R804N, V825D, C844S, L890S, H894Y, L912D, ...Details: Human c-KIT kinase domain (P551-H934) bearing surface mutations to optimise protein expression (I563S, V569S, Y609Q, L631S, M651E, I662H, D768H, R804N, V825D, C844S, L890S, H894Y, L912D, L923D), and the kinase insert domain(S688-D765) deleted and replaced with the sequence EFVPYKVAPEDLYKDFLT Source: (gene. exp.) Homo sapiens (human) / Gene: KIT, SCFR / Production host: Escherichia coli (E. coli) / Strain (production host): Star BL21 (DE3) References: UniProt: P10721, receptor protein-tyrosine kinase #2: Chemical | #3: Water | ChemComp-HOH / | |
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-Experimental details
-Experiment
Experiment | Method: X-RAY DIFFRACTION / Number of used crystals: 1 |
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-Sample preparation
Crystal | Density Matthews: 2.49 Å3/Da / Density % sol: 50.56 % / Description: bar |
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Crystal grow | Temperature: 293 K / Method: vapor diffusion, sitting drop / pH: 7.5 Details: 10 % PEG 4000, 20 % glycerol, 0.1 M HEPES-MOPS pH 7.5, 0.02 M sodium formate, 0.02 M ammonium acetate, 0.02 M sodium citrate tribasic dihydrate, 0.02 M sodium potassium tartrate ...Details: 10 % PEG 4000, 20 % glycerol, 0.1 M HEPES-MOPS pH 7.5, 0.02 M sodium formate, 0.02 M ammonium acetate, 0.02 M sodium citrate tribasic dihydrate, 0.02 M sodium potassium tartrate tetrahydrate, 0.02 M sodium oxamate |
-Data collection
Diffraction | Mean temperature: 100 K |
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Diffraction source | Source: SYNCHROTRON / Site: Diamond / Beamline: I02 / Wavelength: 0.97949 Å |
Detector | Type: DECTRIS PILATUS 6M-F / Detector: PIXEL / Date: Sep 26, 2015 |
Radiation | Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray |
Radiation wavelength | Wavelength: 0.97949 Å / Relative weight: 1 |
Reflection | Resolution: 2.33→89.44 Å / Num. obs: 30591 / % possible obs: 99.5 % / Redundancy: 4.7 % / Biso Wilson estimate: 55.4 Å2 / CC1/2: 0.992 / Rmerge(I) obs: 0.125 / Net I/σ(I): 9.6 |
Reflection shell | Resolution: 2.33→2.45 Å / Redundancy: 4.8 % / Rmerge(I) obs: 0.961 / Mean I/σ(I) obs: 2.3 / Num. unique obs: 4405 / CC1/2: 0.613 / % possible all: 99.8 |
-Processing
Software |
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Refinement | Method to determine structure: MOLECULAR REPLACEMENT Starting model: 4HVS Resolution: 2.33→51.28 Å / Cor.coef. Fo:Fc: 0.937 / Cor.coef. Fo:Fc free: 0.928 / Rfactor Rfree error: 0 / SU R Cruickshank DPI: 0.291 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.304 / SU Rfree Blow DPI: 0.205 / SU Rfree Cruickshank DPI: 0.205
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Displacement parameters | Biso mean: 56.94 Å2
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Refine analyze | Luzzati coordinate error obs: 0.27 Å | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Refinement step | Cycle: 1 / Resolution: 2.33→51.28 Å
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Refine LS restraints |
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LS refinement shell | Resolution: 2.33→2.41 Å / Rfactor Rfree error: 0 / Total num. of bins used: 15
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Refinement TLS params. | Method: refined / Refine-ID: X-RAY DIFFRACTION
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Refinement TLS group |
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