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Yorodumi- PDB-4epx: Discovery of Small Molecules that Bind to K-Ras and Inhibit Sos-m... -
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-Basic information
Entry | Database: PDB / ID: 4epx | ||||||
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Title | Discovery of Small Molecules that Bind to K-Ras and Inhibit Sos-mediated Activation | ||||||
Components | GTPase KRas | ||||||
Keywords | HYDROLASE / small GTPase / Signaling transduction / Raf / Ral / Sos / PI3K / cytosol / binder / Inhibitor of Sos-mediated activation | ||||||
Function / homology | Function and homology information forebrain astrocyte development / negative regulation of epithelial cell differentiation / regulation of synaptic transmission, GABAergic / type I pneumocyte differentiation / epithelial tube branching involved in lung morphogenesis / Rac protein signal transduction / skeletal muscle cell differentiation / positive regulation of Rac protein signal transduction / Signaling by RAS GAP mutants / Signaling by RAS GTPase mutants ...forebrain astrocyte development / negative regulation of epithelial cell differentiation / regulation of synaptic transmission, GABAergic / type I pneumocyte differentiation / epithelial tube branching involved in lung morphogenesis / Rac protein signal transduction / skeletal muscle cell differentiation / positive regulation of Rac protein signal transduction / Signaling by RAS GAP mutants / Signaling by RAS GTPase mutants / Activation of RAS in B cells / positive regulation of glial cell proliferation / RAS signaling downstream of NF1 loss-of-function variants / RUNX3 regulates p14-ARF / SOS-mediated signalling / Activated NTRK3 signals through RAS / Activated NTRK2 signals through RAS / SHC1 events in ERBB4 signaling / GRB2 events in EGFR signaling / EGFR Transactivation by Gastrin / SHC1 events in EGFR signaling / Signalling to RAS / GRB2 events in ERBB2 signaling / SHC-related events triggered by IGF1R / Activated NTRK2 signals through FRS2 and FRS3 / glial cell proliferation / Estrogen-stimulated signaling through PRKCZ / SHC1 events in ERBB2 signaling / SHC-mediated cascade:FGFR3 / MET activates RAS signaling / Signaling by PDGFRA transmembrane, juxtamembrane and kinase domain mutants / Signaling by PDGFRA extracellular domain mutants / SHC-mediated cascade:FGFR2 / PTK6 Regulates RHO GTPases, RAS GTPase and MAP kinases / SHC-mediated cascade:FGFR4 / Signaling by FGFR4 in disease / Erythropoietin activates RAS / SHC-mediated cascade:FGFR1 / protein-membrane adaptor activity / FRS-mediated FGFR3 signaling / Signaling by CSF3 (G-CSF) / Signaling by FLT3 ITD and TKD mutants / homeostasis of number of cells within a tissue / FRS-mediated FGFR2 signaling / Signaling by FGFR3 in disease / FRS-mediated FGFR4 signaling / p38MAPK events / Tie2 Signaling / FRS-mediated FGFR1 signaling / striated muscle cell differentiation / Signaling by FGFR2 in disease / Signaling by FLT3 fusion proteins / FLT3 Signaling / Ras activation upon Ca2+ influx through NMDA receptor / Signaling by FGFR1 in disease / CD209 (DC-SIGN) signaling / NCAM signaling for neurite out-growth / Downstream signal transduction / Constitutive Signaling by Overexpressed ERBB2 / Insulin receptor signalling cascade / Signaling by ERBB2 TMD/JMD mutants / small monomeric GTPase / Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants / G protein activity / VEGFR2 mediated cell proliferation / Constitutive Signaling by EGFRvIII / Signaling by ERBB2 ECD mutants / Signaling by ERBB2 KD Mutants / FCERI mediated MAPK activation / RAF activation / regulation of long-term neuronal synaptic plasticity / Signaling by high-kinase activity BRAF mutants / MAP2K and MAPK activation / visual learning / Signaling by SCF-KIT / cytoplasmic side of plasma membrane / Regulation of RAS by GAPs / RAS processing / Negative regulation of MAPK pathway / Signaling by CSF1 (M-CSF) in myeloid cells / 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 / GDP binding / MAPK cascade / Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants / Signaling by BRAF and RAF1 fusions / DAP12 signaling / Ca2+ pathway / RAF/MAP kinase cascade / gene expression / actin cytoskeleton organization / Ras protein signal transduction / neuron apoptotic process / negative regulation of neuron apoptotic process / mitochondrial outer membrane / positive regulation of protein phosphorylation / Golgi membrane / focal adhesion Similarity search - Function | ||||||
Biological species | Homo sapiens (human) | ||||||
Method | X-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 1.76 Å | ||||||
Authors | Sun, Q. / Burke, J.P. / Phan, J. / Burns, M.C. / Olejniczak, E.T. / Waterson, A.G. / Lee, T. / Rossanese, O.W. / Fesik, S.W. | ||||||
Citation | Journal: Angew.Chem.Int.Ed.Engl. / Year: 2012 Title: Discovery of Small Molecules that Bind to K-Ras and Inhibit Sos-Mediated Activation. Authors: Sun, Q. / Burke, J.P. / Phan, J. / Burns, M.C. / Olejniczak, E.T. / Waterson, A.G. / Lee, T. / Rossanese, O.W. / Fesik, S.W. | ||||||
History |
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-Structure visualization
Structure viewer | Molecule: MolmilJmol/JSmol |
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-Downloads & links
-Download
PDBx/mmCIF format | 4epx.cif.gz | 55.8 KB | Display | PDBx/mmCIF format |
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PDB format | pdb4epx.ent.gz | 37.9 KB | Display | PDB format |
PDBx/mmJSON format | 4epx.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Summary document | 4epx_validation.pdf.gz | 1 MB | Display | wwPDB validaton report |
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Full document | 4epx_full_validation.pdf.gz | 1 MB | Display | |
Data in XML | 4epx_validation.xml.gz | 11.3 KB | Display | |
Data in CIF | 4epx_validation.cif.gz | 16.1 KB | Display | |
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/ep/4epx ftp://data.pdbj.org/pub/pdb/validation_reports/ep/4epx | HTTPS FTP |
-Related structure data
Related structure data | 4eprC 4eptC 4epvSC 4epwC 4epyC C: citing same article (ref.) S: Starting model for refinement |
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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: 19354.824 Da / Num. of mol.: 1 / Mutation: G12V, C118S Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: KRAS, KRAS2, RASK2 / Production host: Escherichia coli (E. coli) / References: UniProt: P01116, small monomeric GTPase |
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#2: Chemical | ChemComp-GDP / |
#3: Chemical | ChemComp-MG / |
#4: Chemical | ChemComp-0QR / |
#5: Water | ChemComp-HOH / |
Sequence details | THE CRYSTALLIZ |
-Experimental details
-Experiment
Experiment | Method: X-RAY DIFFRACTION / Number of used crystals: 1 |
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-Sample preparation
Crystal | Density Matthews: 1.92 Å3/Da / Density % sol: 36.03 % |
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Crystal grow | Temperature: 291 K / Method: vapor diffusion, sitting drop / pH: 4.5 Details: 28% PEG8000, 0.1 M sodium acetate, 5% DMSO, pH 4.5, VAPOR DIFFUSION, SITTING DROP, temperature 291K |
-Data collection
Diffraction | Mean temperature: 100 K |
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Diffraction source | Source: ROTATING ANODE / Type: BRUKER AXS MICROSTAR / Wavelength: 1.5418 Å |
Detector | Type: Bruker Platinum 135 / Detector: CCD / Date: Jan 1, 2010 |
Radiation | Monochromator: Montel confocal, multi-layer mirrors / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray |
Radiation wavelength | Wavelength: 1.5418 Å / Relative weight: 1 |
Reflection | Resolution: 1.76→45.86 Å / Num. all: 15410 / Num. obs: 15330 / % possible obs: 99.5 % / Observed criterion σ(F): 0 / Observed criterion σ(I): -3 / Redundancy: 4.7 % / Rmerge(I) obs: 0.099 / Net I/σ(I): 15.2 |
Reflection shell | Resolution: 1.76→1.79 Å / Redundancy: 2.1 % / Rmerge(I) obs: 0.106 / Mean I/σ(I) obs: 6.8 / % possible all: 93.8 |
-Processing
Software |
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Refinement | Method to determine structure: MOLECULAR REPLACEMENT Starting model: 4EPV Resolution: 1.76→45.86 Å / Cor.coef. Fo:Fc: 0.966 / Cor.coef. Fo:Fc free: 0.949 / SU B: 2.28 / SU ML: 0.074 / Cross valid method: THROUGHOUT / ESU R: 0.122 / ESU R Free: 0.121 / Stereochemistry target values: MAXIMUM LIKELIHOOD / 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 / Solvent model: MASK | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Displacement parameters | Biso mean: 16.773 Å2
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Refinement step | Cycle: LAST / Resolution: 1.76→45.86 Å
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Refine LS restraints |
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LS refinement shell | Resolution: 1.762→1.808 Å / Total num. of bins used: 20
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