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Yorodumi- PDB-5c9c: CRYSTAL STRUCTURE OF BRAF(V600E) IN COMPLEX WITH LY3009120 COMPND -
+Open data
-Basic information
Entry | Database: PDB / ID: 5c9c | ||||||
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Title | CRYSTAL STRUCTURE OF BRAF(V600E) IN COMPLEX WITH LY3009120 COMPND | ||||||
Components | Serine/threonine-protein kinase B-raf | ||||||
Keywords | TRANSFERASE/TRANSFERASE INHIBITOR / TRANSFERASE-TRANSFERASE INHIBITOR complex | ||||||
Function / homology | Function and homology information trehalose metabolism in response to stress / CD4-positive, alpha-beta T cell differentiation / CD4-positive or CD8-positive, alpha-beta T cell lineage commitment / negative regulation of synaptic vesicle exocytosis / head morphogenesis / Signalling to p38 via RIT and RIN / myeloid progenitor cell differentiation / ARMS-mediated activation / SHOC2 M1731 mutant abolishes MRAS complex function / Gain-of-function MRAS complexes activate RAF signaling ...trehalose metabolism in response to stress / CD4-positive, alpha-beta T cell differentiation / CD4-positive or CD8-positive, alpha-beta T cell lineage commitment / negative regulation of synaptic vesicle exocytosis / head morphogenesis / Signalling to p38 via RIT and RIN / myeloid progenitor cell differentiation / ARMS-mediated activation / SHOC2 M1731 mutant abolishes MRAS complex function / Gain-of-function MRAS complexes activate RAF signaling / endothelial cell apoptotic process / negative regulation of fibroblast migration / positive regulation of glucose transmembrane transport / establishment of protein localization to membrane / mitogen-activated protein kinase kinase binding / regulation of T cell differentiation / Negative feedback regulation of MAPK pathway / positive regulation of axonogenesis / Frs2-mediated activation / stress fiber assembly / positive regulation of axon regeneration / face development / synaptic vesicle exocytosis / somatic stem cell population maintenance / thyroid gland development / MAP kinase kinase activity / MAP kinase kinase kinase activity / negative regulation of endothelial cell apoptotic process / positive regulation of substrate adhesion-dependent cell spreading / response to cAMP / positive regulation of stress fiber assembly / ERK1 and ERK2 cascade / cellular response to calcium ion / substrate adhesion-dependent cell spreading / cellular response to nerve growth factor stimulus / thymus development / long-term synaptic potentiation / animal organ morphogenesis / Spry regulation of FGF signaling / RAF activation / Signaling by high-kinase activity BRAF mutants / visual learning / MAP2K and MAPK activation / epidermal growth factor receptor signaling pathway / response to peptide hormone / Negative regulation of MAPK pathway / Signaling by RAF1 mutants / Signaling by moderate kinase activity BRAF mutants / Paradoxical activation of RAF signaling by kinase inactive BRAF / Signaling downstream of RAS mutants / MAPK cascade / Signaling by BRAF and RAF1 fusions / cellular response to xenobiotic stimulus / presynapse / positive regulation of peptidyl-serine phosphorylation / T cell differentiation in thymus / cell body / regulation of cell population proliferation / T cell receptor signaling pathway / scaffold protein binding / negative regulation of neuron apoptotic process / positive regulation of ERK1 and ERK2 cascade / non-specific serine/threonine protein kinase / protein kinase activity / neuron projection / protein phosphorylation / protein serine kinase activity / intracellular membrane-bounded organelle / protein serine/threonine kinase activity / calcium ion binding / protein-containing complex binding / positive regulation of gene expression / negative regulation of apoptotic process / mitochondrion / ATP binding / identical protein binding / nucleus / plasma membrane / cytosol Similarity search - Function | ||||||
Biological species | Homo sapiens (human) | ||||||
Method | X-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.7 Å | ||||||
Authors | Edwards, T. / Abendroth, J. / Chun, L. | ||||||
Citation | Journal: Cancer Cell / Year: 2015 Title: Inhibition of RAF Isoforms and Active Dimers by LY3009120 Leads to Anti-tumor Activities in RAS or BRAF Mutant Cancers. Authors: Peng, S.B. / Henry, J.R. / Kaufman, M.D. / Lu, W.P. / Smith, B.D. / Vogeti, S. / Rutkoski, T.J. / Wise, S. / Chun, L. / Zhang, Y. / Van Horn, R.D. / Yin, T. / Zhang, X. / Yadav, V. / Chen, S. ...Authors: Peng, S.B. / Henry, J.R. / Kaufman, M.D. / Lu, W.P. / Smith, B.D. / Vogeti, S. / Rutkoski, T.J. / Wise, S. / Chun, L. / Zhang, Y. / Van Horn, R.D. / Yin, T. / Zhang, X. / Yadav, V. / Chen, S.H. / Gong, X. / Ma, X. / Webster, Y. / Buchanan, S. / Mochalkin, I. / Huber, L. / Kays, L. / Donoho, G.P. / Walgren, J. / McCann, D. / Patel, P. / Conti, I. / Plowman, G.D. / Starling, J.J. / Flynn, D.L. #1: Journal: J.Med.Chem. / Year: 2015 Title: Discovery of 1-(3,3-dimethylbutyl)-3-(2-fluoro-4-methyl-5-(7-methyl-2-(methylamino)pyrido[2,3-d]pyrimidin-6-yl)phenyl)urea (LY3009120) as a pan-RAF inhibitor with minimal paradoxical ...Title: Discovery of 1-(3,3-dimethylbutyl)-3-(2-fluoro-4-methyl-5-(7-methyl-2-(methylamino)pyrido[2,3-d]pyrimidin-6-yl)phenyl)urea (LY3009120) as a pan-RAF inhibitor with minimal paradoxical activation and activity against BRAF or RAS mutant tumor cells. Authors: Henry, J.R. / Kaufman, M.D. / Peng, S.B. / Ahn, Y.M. / Caldwell, T.M. / Vogeti, L. / Telikepalli, H. / Lu, W.P. / Hood, M.M. / Rutkoski, T.J. / Smith, B.D. / Vogeti, S. / Miller, D. / Wise, ...Authors: Henry, J.R. / Kaufman, M.D. / Peng, S.B. / Ahn, Y.M. / Caldwell, T.M. / Vogeti, L. / Telikepalli, H. / Lu, W.P. / Hood, M.M. / Rutkoski, T.J. / Smith, B.D. / Vogeti, S. / Miller, D. / Wise, S.C. / Chun, L. / Zhang, X. / Zhang, Y. / Kays, L. / Hipskind, P.A. / Wrobleski, A.D. / Lobb, K.L. / Clay, J.M. / Cohen, J.D. / Walgren, J.L. / McCann, D. / Patel, P. / Clawson, D.K. / Guo, S. / Manglicmot, D. / Groshong, C. / Logan, C. / Starling, J.J. / 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 | 5c9c.cif.gz | 118.9 KB | Display | PDBx/mmCIF format |
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PDB format | pdb5c9c.ent.gz | 89.5 KB | Display | PDB format |
PDBx/mmJSON format | 5c9c.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/c9/5c9c ftp://data.pdbj.org/pub/pdb/validation_reports/c9/5c9c | HTTPS FTP |
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-Related structure data
Related structure data | 1uwhS S: Starting model for refinement |
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Similar structure data |
-Links
-Assembly
Deposited unit |
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2 |
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3 |
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Unit cell |
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-Components
#1: Protein | Mass: 35247.617 Da / Num. of mol.: 2 / Fragment: unp residues 432-726 / Mutation: V600E Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: BRAF, BRAF1, RAFB1 / Production host: Trichoplusia ni (cabbage looper) References: UniProt: P15056, non-specific serine/threonine protein kinase #2: Chemical | #3: Chemical | ChemComp-CL / | #4: 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: 2.59 Å3/Da / Density % sol: 52.5 % |
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Crystal grow | Temperature: 289 K / Method: vapor diffusion, sitting drop Details: 26% PEG 3350, 50 MM AMMONIUM CITRATE, 50 MM SODIUM FLORIDE, 2 MG/ML PROTEIN, 5-FOLD MOLAR EXCESS DP4978; CRYSTAL ID 215552F10, SITTING DROP VAPOR DIFFUSION, TEMPERATURE 289K |
-Data collection
Diffraction | Mean temperature: 100 K |
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Diffraction source | Source: SYNCHROTRON / Site: ALS / Beamline: 5.0.2 / Wavelength: 1 Å |
Detector | Type: ADSC QUANTUM 315r / Detector: CCD / Date: Jun 11, 2010 |
Radiation | Monochromator: Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray |
Radiation wavelength | Wavelength: 1 Å / Relative weight: 1 |
Reflection | Resolution: 2.7→50 Å / Num. obs: 20853 / % possible obs: 99.1 % / Observed criterion σ(I): -3 / Redundancy: 6.2 % / Biso Wilson estimate: 33.92 Å2 / Rmerge(I) obs: 0.127 / Net I/σ(I): 12.25 |
Reflection shell | Resolution: 2.7→2.77 Å / Redundancy: 6.1 % / Rmerge(I) obs: 0.591 / Mean I/σ(I) obs: 2.9 / % possible all: 99.9 |
-Processing
Software |
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Refinement | Method to determine structure: MOLECULAR REPLACEMENT Starting model: 1uwh Resolution: 2.7→50 Å / Cor.coef. Fo:Fc: 0.938 / Cor.coef. Fo:Fc free: 0.902 / SU B: 9.913 / SU ML: 0.205 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.623 / ESU R Free: 0.301 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE
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Solvent computation | Ion probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Displacement parameters | Biso mean: 24.92 Å2
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Refinement step | Cycle: LAST / Resolution: 2.7→50 Å
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Refine LS restraints |
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