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Yorodumi- PDB-6p8w: Crystal structure of human KRAS G12C covalently bound to an acryl... -
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-Basic information
Entry | Database: PDB / ID: 6p8w | ||||||
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Title | Crystal structure of human KRAS G12C covalently bound to an acryloylazetidine acetamide inhibitor. | ||||||
Components | GTPase KRas | ||||||
Keywords | SIGNALING PROTEIN/Inhibitor / Inhibitor / GTPase / SIGNALING PROTEIN / SIGNALING PROTEIN-Inhibitor complex | ||||||
Function / homology | Function and homology information forebrain astrocyte development / negative regulation of epithelial cell differentiation / regulation of synaptic transmission, GABAergic / epithelial tube branching involved in lung morphogenesis / type I pneumocyte differentiation / 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 / epithelial tube branching involved in lung morphogenesis / type I pneumocyte differentiation / 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 / 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 / Signalling to RAS / glial cell proliferation / SHC-related events triggered by IGF1R / Activated NTRK2 signals through FRS2 and FRS3 / Estrogen-stimulated signaling through PRKCZ / SHC-mediated cascade:FGFR3 / MET activates RAS signaling / 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 / GRB2 events in EGFR signaling / SHC1 events in EGFR signaling / EGFR Transactivation by Gastrin / Signaling by FLT3 fusion proteins / FLT3 Signaling / 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 / Constitutive Signaling by Overexpressed ERBB2 / Insulin receptor signalling cascade / small monomeric GTPase / G protein activity / Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants / VEGFR2 mediated cell proliferation / FCERI mediated MAPK activation / Signaling by ERBB2 TMD/JMD mutants / regulation of long-term neuronal synaptic plasticity / RAF activation / Signaling by high-kinase activity BRAF mutants / Constitutive Signaling by EGFRvIII / visual learning / MAP2K and MAPK activation / Signaling by ERBB2 ECD mutants / Signaling by ERBB2 KD Mutants / Signaling by SCF-KIT / cytoplasmic side of plasma membrane / Regulation of RAS by GAPs / Negative regulation of MAPK pathway / RAS processing / Signaling by RAF1 mutants / GDP binding / Signaling by moderate kinase activity BRAF mutants / Paradoxical activation of RAF signaling by kinase inactive BRAF / Signaling downstream of RAS mutants / Signaling by CSF1 (M-CSF) in myeloid cells / MAPK cascade / Signaling by BRAF and RAF1 fusions / DAP12 signaling / Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants / Ca2+ pathway / gene expression / actin cytoskeleton organization / RAF/MAP kinase cascade / neuron apoptotic process / mitochondrial outer membrane / negative regulation of neuron apoptotic process / Ras protein signal transduction / positive regulation of protein phosphorylation / Golgi membrane / focal adhesion Similarity search - Function | ||||||
Biological species | Homo sapiens (human) | ||||||
Method | X-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.1 Å | ||||||
Authors | Mohr, C. | ||||||
Citation | Journal: Acs Med.Chem.Lett. / Year: 2019 Title: Discovery ofN-(1-Acryloylazetidin-3-yl)-2-(1H-indol-1-yl)acetamides as Covalent Inhibitors of KRASG12C. Authors: Shin, Y. / Jeong, J.W. / Wurz, R.P. / Achanta, P. / Arvedson, T. / Bartberger, M.D. / Campuzano, I.D.G. / Fucini, R. / Hansen, S.K. / Ingersoll, J. / Iwig, J.S. / Lipford, J.R. / Ma, V. / ...Authors: Shin, Y. / Jeong, J.W. / Wurz, R.P. / Achanta, P. / Arvedson, T. / Bartberger, M.D. / Campuzano, I.D.G. / Fucini, R. / Hansen, S.K. / Ingersoll, J. / Iwig, J.S. / Lipford, J.R. / Ma, V. / Kopecky, D.J. / McCarter, J. / San Miguel, T. / Mohr, C. / Sabet, S. / Saiki, A.Y. / Sawayama, A. / Sethofer, S. / Tegley, C.M. / Volak, L.P. / Yang, K. / Lanman, B.A. / Erlanson, D.A. / Cee, V.J. | ||||||
History |
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-Structure visualization
Structure viewer | Molecule: MolmilJmol/JSmol |
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-Downloads & links
-Download
PDBx/mmCIF format | 6p8w.cif.gz | 85.7 KB | Display | PDBx/mmCIF format |
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PDB format | pdb6p8w.ent.gz | 67.2 KB | Display | PDB format |
PDBx/mmJSON format | 6p8w.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/p8/6p8w ftp://data.pdbj.org/pub/pdb/validation_reports/p8/6p8w | HTTPS FTP |
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-Related structure data
-Links
-Assembly
Deposited unit |
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1 |
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2 |
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Unit cell |
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Noncrystallographic symmetry (NCS) | NCS domain:
NCS domain segments:
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-Components
#1: Protein | Mass: 21038.613 Da / Num. of mol.: 2 / Mutation: C51S,C80L,C118S Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: KRAS, KRAS2, RASK2 / Variant: VAR_006839 G12C / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: P01116 #2: Chemical | ChemComp-CA / #3: Chemical | #4: Chemical | #5: Water | ChemComp-HOH / | Has ligand of interest | Y | |
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-Experimental details
-Experiment
Experiment | Method: X-RAY DIFFRACTION / Number of used crystals: 1 |
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-Sample preparation
Crystal grow | Temperature: 293 K / Method: vapor diffusion, sitting drop / pH: 6.5 / Details: 0.2M Calcium chloride, 0.1M MES pH6.5, 30% PEG4000 |
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-Data collection
Diffraction | Mean temperature: 100 K / Serial crystal experiment: N |
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Diffraction source | Source: ROTATING ANODE / Type: RIGAKU FR-E SUPERBRIGHT / Wavelength: 1.5418 Å |
Detector | Type: RIGAKU SATURN 92 / Detector: CCD / Date: May 27, 2015 / Details: VariMax HF |
Radiation | Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray |
Radiation wavelength | Wavelength: 1.5418 Å / Relative weight: 1 |
Reflection | Resolution: 2.1→30 Å / Num. obs: 17067 / % possible obs: 93.9 % / Redundancy: 1.9 % / Rpim(I) all: 0.068 / Rrim(I) all: 0.096 / Rsym value: 0.068 / Χ2: 1 / Net I/σ(I): 10.2 |
Reflection shell | Resolution: 2.1→2.18 Å / Redundancy: 1.8 % / Mean I/σ(I) obs: 3.05 / Num. unique obs: 1370 / CC1/2: 0.837 / Rpim(I) all: 0.246 / Rrim(I) all: 0.348 / Rsym value: 0.246 / Χ2: 1 / % possible all: 78.5 |
-Processing
Software |
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Refinement | Method to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.1→30 Å / Cor.coef. Fo:Fc: 0.931 / Cor.coef. Fo:Fc free: 0.903 / SU B: 7.74 / SU ML: 0.206 / Cross valid method: THROUGHOUT / ESU R: 0.463 / ESU R Free: 0.266 / 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: 30.215 Å2
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Refinement step | Cycle: 1 / Resolution: 2.1→30 Å
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Refine LS restraints |
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