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Yorodumi- PDB-8dni: Crystal structure of human KRAS G12C covalently bound with Araxes... -
+Open data
-Basic information
Entry | Database: PDB / ID: 8dni | ||||||
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Title | Crystal structure of human KRAS G12C covalently bound with Araxes WO2020/028706A1 compound I-1 | ||||||
Components | GTPase KRas | ||||||
Keywords | SIGNALING PROTEIN / Inhibitor / GTPase | ||||||
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 / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.5 Å | ||||||
Authors | Mohr, C. | ||||||
Funding support | 1items
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Citation | Journal: J.Comput.Aided Mol.Des. / Year: 2022 Title: Modeling receptor flexibility in the structure-based design of KRAS G12C inhibitors. Authors: Zhu, K. / Li, C. / Wu, K.Y. / Mohr, C. / Li, X. / Lanman, B. | ||||||
History |
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-Structure visualization
Structure viewer | Molecule: MolmilJmol/JSmol |
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-Downloads & links
-Download
PDBx/mmCIF format | 8dni.cif.gz | 57 KB | Display | PDBx/mmCIF format |
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PDB format | pdb8dni.ent.gz | 36.8 KB | Display | PDB format |
PDBx/mmJSON format | 8dni.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Summary document | 8dni_validation.pdf.gz | 1 MB | Display | wwPDB validaton report |
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Full document | 8dni_full_validation.pdf.gz | 1 MB | Display | |
Data in XML | 8dni_validation.xml.gz | 10.6 KB | Display | |
Data in CIF | 8dni_validation.cif.gz | 14.7 KB | Display | |
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/dn/8dni ftp://data.pdbj.org/pub/pdb/validation_reports/dn/8dni | HTTPS FTP |
-Related structure data
Related structure data | 8dnjC 8dnkC 6oimS S: Starting model for refinement C: citing same article (ref.) |
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Similar structure data | Similarity search - Function & homologyF&H Search |
-Links
-Assembly
Deposited unit |
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1 |
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Unit cell |
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Components on special symmetry positions |
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-Components
#1: Protein | Mass: 21038.613 Da / Num. of mol.: 1 / Mutation: C51S,C80L,C118S Source method: isolated from a genetically manipulated source Details: G12C variant / Source: (gene. exp.) Homo sapiens (human) / Gene: KRAS, KRAS2, RASK2 / Variant: VAR_006839 G12C / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: P01116 |
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#2: Chemical | ChemComp-MG / |
#3: Chemical | ChemComp-GDP / |
#4: Chemical | ChemComp-U4L / ( |
#5: Water | ChemComp-HOH / |
Has ligand of interest | Y |
-Experimental details
-Experiment
Experiment | Method: X-RAY DIFFRACTION / Number of used crystals: 1 |
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-Sample preparation
Crystal | Density Matthews: 2.03 Å3/Da / Density % sol: 39.39 % |
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Crystal grow | Temperature: 293 K / Method: vapor diffusion, sitting drop / pH: 6.5 / Details: 0.001M MgCl2, 0.1M MES pH6.5, 30% PEG4000 |
-Data collection
Diffraction | Mean temperature: 100 K / Serial crystal experiment: N |
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Diffraction source | Source: SYNCHROTRON / Site: ALS / Beamline: 5.0.2 / Wavelength: 1 Å |
Detector | Type: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Mar 13, 2020 |
Radiation | Monochromator: Double-crystal, Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray |
Radiation wavelength | Wavelength: 1 Å / Relative weight: 1 |
Reflection | Resolution: 1.5→30 Å / Num. obs: 30081 / % possible obs: 100 % / Redundancy: 31 % / CC1/2: 1 / Rmerge(I) obs: 0.118 / Net I/σ(I): 8.1 |
Reflection shell | Resolution: 1.5→1.55 Å / Redundancy: 30.7 % / Rmerge(I) obs: 0.885 / Mean I/σ(I) obs: 5 / Num. unique obs: 2882 / CC1/2: 0.936 / % possible all: 100 |
-Processing
Software |
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Refinement | Method to determine structure: MOLECULAR REPLACEMENT Starting model: 6OIM Resolution: 1.5→30 Å / Cor.coef. Fo:Fc: 0.93 / Cor.coef. Fo:Fc free: 0.919 / SU B: 1.759 / SU ML: 0.067 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.101 / ESU R Free: 0.093 / Stereochemistry target values: MAXIMUM LIKELIHOOD Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
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Solvent computation | Ion probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Displacement parameters | Biso max: 41.91 Å2 / Biso mean: 13.739 Å2 / Biso min: 5.52 Å2
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Refinement step | Cycle: final / Resolution: 1.5→30 Å
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Refine LS restraints |
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LS refinement shell | Resolution: 1.5→1.539 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
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