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Yorodumi- PDB-6mob: Crystal structure of KIT1 in complex with DP2976 via co-crystalli... -
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-Basic information
Entry | Database: PDB / ID: 6mob | ||||||
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Title | Crystal structure of KIT1 in complex with DP2976 via co-crystallization | ||||||
Components | Mast/stem cell growth factor receptor Kit | ||||||
Keywords | TRANSFERASE/TRANSFERASE INHIBITOR / Deciphera / Kit1 kinase / DP2976 / decode / TRANSFERASE-TRANSFERASE INHIBITOR complex | ||||||
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 / positive regulation of mast cell cytokine production / immature B cell differentiation / melanocyte differentiation / germ cell migration / lymphoid progenitor cell differentiation / myeloid progenitor cell differentiation / digestive tract development / negative regulation of programmed cell death / embryonic hemopoiesis / lamellipodium assembly / pigmentation / tongue development / megakaryocyte development / Regulation of KIT signaling / mast cell degranulation / stem cell population maintenance / positive regulation of Notch signaling pathway / cytokine binding / negative regulation of reproductive process / negative regulation of developmental process / spermatid development / growth factor binding / somatic stem cell population maintenance / hemopoiesis / T cell differentiation / ectopic germ cell programmed cell death / hematopoietic progenitor cell differentiation / positive regulation of phospholipase C activity / 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 / cell chemotaxis / B cell differentiation / erythrocyte differentiation / 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 / cytoplasmic side of plasma membrane / receptor protein-tyrosine kinase / fibrillar center / cytokine-mediated signaling pathway / male gonad development / Constitutive Signaling by Aberrant PI3K in Cancer / positive regulation of DNA-binding transcription factor activity / 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: 1.8 Å | ||||||
Authors | Edwards, T.E. / Abendroth, J. / Safford, K. / Chun, L. | ||||||
Citation | Journal: Cancer Cell / Year: 2019 Title: Ripretinib (DCC-2618) Is a Switch Control Kinase Inhibitor of a Broad Spectrum of Oncogenic and Drug-Resistant KIT and PDGFRA Variants. Authors: Smith, B.D. / Kaufman, M.D. / Lu, W.P. / Gupta, A. / Leary, C.B. / Wise, S.C. / Rutkoski, T.J. / Ahn, Y.M. / Al-Ani, G. / Bulfer, S.L. / Caldwell, T.M. / Chun, L. / Ensinger, C.L. / Hood, M. ...Authors: Smith, B.D. / Kaufman, M.D. / Lu, W.P. / Gupta, A. / Leary, C.B. / Wise, S.C. / Rutkoski, T.J. / Ahn, Y.M. / Al-Ani, G. / Bulfer, S.L. / Caldwell, T.M. / Chun, L. / Ensinger, C.L. / Hood, M.M. / McKinley, A. / Patt, W.C. / Ruiz-Soto, R. / Su, Y. / Telikepalli, H. / Town, A. / Turner, B.A. / Vogeti, L. / Vogeti, S. / Yates, K. / Janku, F. / Abdul Razak, A.R. / Rosen, O. / Heinrich, M.C. / Flynn, D.L. | ||||||
History |
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-Structure visualization
Structure viewer | Molecule: MolmilJmol/JSmol |
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-Downloads & links
-Download
PDBx/mmCIF format | 6mob.cif.gz | 88.4 KB | Display | PDBx/mmCIF format |
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PDB format | pdb6mob.ent.gz | 64.6 KB | Display | PDB format |
PDBx/mmJSON format | 6mob.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/mo/6mob ftp://data.pdbj.org/pub/pdb/validation_reports/mo/6mob | HTTPS FTP |
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-Related structure data
Similar structure data |
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-Links
-Assembly
Deposited unit |
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1 |
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Unit cell |
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-Components
#1: Protein | Mass: 35331.887 Da / Num. of mol.: 1 / Fragment: UNP residues 566-693,754-935 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: KIT, SCFR / Plasmid: pBACgus / Production host: Trichoplusia ni (cabbage looper) / Strain (production host): TniPro References: UniProt: P10721, receptor protein-tyrosine kinase | ||||
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#2: Chemical | ChemComp-NO3 / #3: Chemical | ChemComp-JWY / | #4: 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: 3.34 Å3/Da / Density % sol: 63.2 % |
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Crystal grow | Temperature: 289 K / Method: vapor diffusion, sitting drop Details: 12 mg/mL Kit1 protein in 20 mM Tris pH 8.0, 0.25 M sodium chloride, 5 mM imidazole, 5 mM DTT, 1 mM EDTA, crystallant: 2.5 M ammonium nitrate, 0.1 M sodium acetate, pH 4.6, 5-fold molar ...Details: 12 mg/mL Kit1 protein in 20 mM Tris pH 8.0, 0.25 M sodium chloride, 5 mM imidazole, 5 mM DTT, 1 mM EDTA, crystallant: 2.5 M ammonium nitrate, 0.1 M sodium acetate, pH 4.6, 5-fold molar excess DP2976, Crystal ID 204905d1 |
-Data collection
Diffraction | Mean temperature: 100 K / Serial crystal experiment: N |
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Diffraction source | Source: SYNCHROTRON / Site: CLSI / Beamline: 08ID-1 / Wavelength: 0.9795 Å |
Detector | Type: RAYONIX MX-300 / Detector: CCD / Date: Sep 17, 2009 |
Radiation | Monochromator: DCM with cryo-cooled 1st crystal sagittally bent 2nd crystal followed by vertically focusing mirror Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray |
Radiation wavelength | Wavelength: 0.9795 Å / Relative weight: 1 |
Reflection | Resolution: 1.8→50 Å / Num. obs: 43821 / % possible obs: 96.5 % / Redundancy: 5 % / Rmerge(I) obs: 0.056 / Χ2: 1.034 / Net I/σ(I): 24.7 |
Reflection shell | Resolution: 1.8→1.86 Å / Redundancy: 4.9 % / Rmerge(I) obs: 0.49 / Mean I/σ(I) obs: 3.52 / Num. unique obs: 4487 / Χ2: 0.97 / % possible all: 98.4 |
-Processing
Software |
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Refinement | Method to determine structure: MOLECULAR REPLACEMENT Starting model: Beryllium, internal model Resolution: 1.8→50 Å / Cor.coef. Fo:Fc: 0.961 / Cor.coef. Fo:Fc free: 0.951 / SU B: 2.064 / SU ML: 0.065 / SU R Cruickshank DPI: 0.1031 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.104 / ESU R Free: 0.102 / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
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Solvent computation | Ion probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Displacement parameters | Biso max: 67 Å2 / Biso mean: 25.35 Å2 / Biso min: 10.54 Å2
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Refinement step | Cycle: final / Resolution: 1.8→50 Å
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Refine LS restraints |
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LS refinement shell | Resolution: 1.8→1.84 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
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