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Yorodumi- PDB-6epl: Ras guanine exchange factor SOS1 (Rem-cdc25) in complex with KRAS... -
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-Basic information
Entry | Database: PDB / ID: 6epl | ||||||
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Title | Ras guanine exchange factor SOS1 (Rem-cdc25) in complex with KRAS(G12C) | ||||||
Components |
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Keywords | SIGNALING PROTEIN / Guanine nucleotide exchange factor / GEF / GTPASE / surface mutation | ||||||
Function / homology | Function and homology information midbrain morphogenesis / regulation of pro-B cell differentiation / vitellogenesis / pericardium morphogenesis / cardiac atrium morphogenesis / heart trabecula morphogenesis / regulation of T cell differentiation in thymus / GTPase complex / positive regulation of small GTPase mediated signal transduction / Interleukin-15 signaling ...midbrain morphogenesis / regulation of pro-B cell differentiation / vitellogenesis / pericardium morphogenesis / cardiac atrium morphogenesis / heart trabecula morphogenesis / regulation of T cell differentiation in thymus / GTPase complex / positive regulation of small GTPase mediated signal transduction / Interleukin-15 signaling / Activation of RAC1 / blood vessel morphogenesis / forebrain astrocyte development / positive regulation of epidermal growth factor receptor signaling pathway / negative regulation of epithelial cell differentiation / regulation of synaptic transmission, GABAergic / epithelial tube branching involved in lung morphogenesis / epidermal growth factor receptor binding / Regulation of KIT signaling / type I pneumocyte differentiation / leukocyte migration / NRAGE signals death through JNK / regulation of T cell proliferation / roof of mouth development / Rac protein signal transduction / eyelid development in camera-type eye / skeletal muscle cell differentiation / positive regulation of Rac protein signal transduction / Fc-epsilon receptor signaling pathway / Signaling by RAS GAP mutants / Signaling by RAS GTPase mutants / Activation of RAS in B cells / neurotrophin TRK receptor signaling pathway / GRB2:SOS provides linkage to MAPK signaling for Integrins / B cell homeostasis / RAS signaling downstream of NF1 loss-of-function variants / RUNX3 regulates p14-ARF / SOS-mediated signalling / RET signaling / Activated NTRK3 signals through RAS / Activated NTRK2 signals through RAS / hair follicle development / SHC1 events in ERBB4 signaling / Signalling to RAS / fibroblast growth factor receptor signaling pathway / glial cell proliferation / SHC-related events triggered by IGF1R / Activated NTRK2 signals through FRS2 and FRS3 / Role of LAT2/NTAL/LAB on calcium mobilization / Signal attenuation / Estrogen-stimulated signaling through PRKCZ / Interleukin receptor SHC signaling / SHC-mediated cascade:FGFR3 / MET activates RAS signaling / Schwann cell development / PTK6 Regulates RHO GTPases, RAS GTPase and MAP kinases / Signaling by PDGFRA transmembrane, juxtamembrane and kinase domain mutants / Signaling by PDGFRA extracellular domain mutants / SHC-mediated cascade:FGFR2 / SHC-mediated cascade:FGFR4 / Signaling by FGFR4 in disease / SHC-mediated cascade:FGFR1 / Erythropoietin activates RAS / protein-membrane adaptor activity / FRS-mediated FGFR3 signaling / Signaling by CSF3 (G-CSF) / positive regulation of glial cell proliferation / Signaling by FLT3 ITD and TKD mutants / homeostasis of number of cells within a tissue / FRS-mediated FGFR2 signaling / FRS-mediated FGFR4 signaling / Signaling by FGFR3 in disease / FRS-mediated FGFR1 signaling / p38MAPK events / Tie2 Signaling / Signaling by FGFR2 in disease / striated muscle cell differentiation / RAC1 GTPase cycle / GRB2 events in EGFR signaling / SHC1 events in EGFR signaling / EGFR Transactivation by Gastrin / Signaling by FLT3 fusion proteins / FLT3 Signaling / myelination / Signaling by FGFR1 in disease / Ras activation upon Ca2+ influx through NMDA receptor / GRB2 events in ERBB2 signaling / NCAM signaling for neurite out-growth / CD209 (DC-SIGN) signaling / SHC1 events in ERBB2 signaling / Downstream signal transduction / FCERI mediated Ca+2 mobilization / Constitutive Signaling by Overexpressed ERBB2 / Insulin receptor signalling cascade / GTPase activator activity / guanyl-nucleotide exchange factor activity / small monomeric GTPase / insulin-like growth factor receptor signaling pathway / G protein activity / Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants Similarity search - Function | ||||||
Biological species | Homo sapiens (human) | ||||||
Method | X-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.55 Å | ||||||
Authors | Hillig, R.C. / Moosmayer, D. / Hilpmann, A. / Bader, B. / Schroeder, J. / Wortmann, L. / Sautier, B. / Briem, H. / Petersen, K. / Badock, V. | ||||||
Citation | Journal: Proc. Natl. Acad. Sci. U.S.A. / Year: 2019 Title: Discovery of potent SOS1 inhibitors that block RAS activation via disruption of the RAS-SOS1 interaction. Authors: Hillig, R.C. / Sautier, B. / Schroeder, J. / Moosmayer, D. / Hilpmann, A. / Stegmann, C.M. / Werbeck, N.D. / Briem, H. / Boemer, U. / Weiske, J. / Badock, V. / Mastouri, J. / Petersen, K. / ...Authors: Hillig, R.C. / Sautier, B. / Schroeder, J. / Moosmayer, D. / Hilpmann, A. / Stegmann, C.M. / Werbeck, N.D. / Briem, H. / Boemer, U. / Weiske, J. / Badock, V. / Mastouri, J. / Petersen, K. / Siemeister, G. / Kahmann, J.D. / Wegener, D. / Bohnke, N. / Eis, K. / Graham, K. / Wortmann, L. / von Nussbaum, F. / Bader, B. | ||||||
History |
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-Structure visualization
Structure viewer | Molecule: MolmilJmol/JSmol |
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-Downloads & links
-Download
PDBx/mmCIF format | 6epl.cif.gz | 278.7 KB | Display | PDBx/mmCIF format |
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PDB format | pdb6epl.ent.gz | 224.6 KB | Display | PDB format |
PDBx/mmJSON format | 6epl.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/ep/6epl ftp://data.pdbj.org/pub/pdb/validation_reports/ep/6epl | HTTPS FTP |
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-Related structure data
Related structure data | 5ovdC 5oveC 5ovfC 5ovgC 5ovhC 5oviC 6eieC 6epmC 6epnC 6epoC 6eppC 1bkdS 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: 19386.850 Da / Num. of mol.: 1 / Mutation: G12C, C118S, D126E, T127S, K128R Source method: isolated from a genetically manipulated source Details: N-terminal G is a cloning artifact / Source: (gene. exp.) Homo sapiens (human) / Gene: KRAS, KRAS2, RASK2 / Production host: Escherichia coli (E. coli) / References: UniProt: P01116 |
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#2: Protein | Mass: 57103.285 Da / Num. of mol.: 1 / Mutation: K563G Source method: isolated from a genetically manipulated source Details: Mutation K563G is a cloning artifact / Source: (gene. exp.) Homo sapiens (human) / Gene: SOS1 / Production host: Escherichia coli (E. coli) / References: UniProt: Q07889 |
#3: Chemical | ChemComp-GOL / |
#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: 3.69 Å3/Da / Density % sol: 66.68 % |
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Crystal grow | Temperature: 277 K / Method: vapor diffusion, hanging drop / pH: 7.5 Details: Drops made from KRAS SOS1 complex (11.3 mg/ml in 5 mM Tris pH 7.5, 100 mM NaCl) and reservoir solution (3.65 M sodium Formate). No cryo protectant added. |
-Data collection
Diffraction | Mean temperature: 100 K |
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Diffraction source | Source: SYNCHROTRON / Site: BESSY / Beamline: 14.1 / Wavelength: 0.91841 Å |
Detector | Type: DECTRIS PILATUS3 S 6M / Detector: PIXEL / Date: Jan 23, 2014 |
Radiation | Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray |
Radiation wavelength | Wavelength: 0.91841 Å / Relative weight: 1 |
Reflection | Resolution: 2.55→48.4 Å / Num. obs: 37373 / % possible obs: 99 % / Redundancy: 9.5 % / Biso Wilson estimate: 44 Å2 / CC1/2: 0.997 / Rrim(I) all: 0.164 / Rsym value: 0.155 / Net I/σ(I): 13 |
Reflection shell | Resolution: 2.55→2.7 Å / Redundancy: 8.6 % / Mean I/σ(I) obs: 2.2 / Num. unique obs: 5894 / CC1/2: 0.592 / Rrim(I) all: 0.942 / Rsym value: 0.885 / % possible all: 98.3 |
-Processing
Software |
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Refinement | Method to determine structure: MOLECULAR REPLACEMENT Starting model: 1BKD Resolution: 2.55→48.39 Å / Cor.coef. Fo:Fc: 0.95 / Cor.coef. Fo:Fc free: 0.928 / SU B: 16.66 / SU ML: 0.18 / Cross valid method: THROUGHOUT / ESU R: 0.315 / ESU R Free: 0.229 / 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: 1.2 Å | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Displacement parameters | Biso mean: 49.401 Å2
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Refinement step | Cycle: 1 / Resolution: 2.55→48.39 Å
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Refine LS restraints |
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