+Open data
-Basic information
Entry | Database: PDB / ID: 6t5v | ||||||
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Title | KRasG12C ligand complex | ||||||
Components | GTPase KRas | ||||||
Keywords | SIGNALING PROTEIN / GTPase | ||||||
Function / homology | Function and homology information forebrain astrocyte development / regulation of synaptic transmission, GABAergic / negative regulation of epithelial cell differentiation / 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 / regulation of synaptic transmission, GABAergic / negative regulation of epithelial cell differentiation / 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 / homeostasis of number of cells within a tissue / protein-membrane adaptor activity / positive regulation of glial cell proliferation / FRS-mediated FGFR3 signaling / Signaling by CSF3 (G-CSF) / Signaling by FLT3 ITD and TKD mutants / FRS-mediated FGFR2 signaling / FRS-mediated FGFR4 signaling / Signaling by FGFR3 in disease / p38MAPK events / FRS-mediated FGFR1 signaling / 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 / Ras activation upon Ca2+ influx through NMDA receptor / GRB2 events in ERBB2 signaling / Signaling by FGFR1 in disease / 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 / GDP binding / 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 / Signaling by CSF1 (M-CSF) in myeloid cells / MAPK cascade / Signaling by BRAF and RAF1 fusions / Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants / DAP12 signaling / Ca2+ pathway / gene expression / actin cytoskeleton organization / RAF/MAP kinase cascade / neuron apoptotic process / Ras protein signal transduction / mitochondrial outer membrane / negative regulation of neuron apoptotic process / 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: 1.31 Å | ||||||
Authors | Phillips, C. | ||||||
Citation | Journal: J.Med.Chem. / Year: 2020 Title: Structure-Based Design and Pharmacokinetic Optimization of Covalent Allosteric Inhibitors of the Mutant GTPase KRASG12C. Authors: Kettle, J.G. / Bagal, S.K. / Bickerton, S. / Bodnarchuk, M.S. / Breed, J. / Carbajo, R.J. / Cassar, D.J. / Chakraborty, A. / Cosulich, S. / Cumming, I. / Davies, M. / Eatherton, A. / Evans, ...Authors: Kettle, J.G. / Bagal, S.K. / Bickerton, S. / Bodnarchuk, M.S. / Breed, J. / Carbajo, R.J. / Cassar, D.J. / Chakraborty, A. / Cosulich, S. / Cumming, I. / Davies, M. / Eatherton, A. / Evans, L. / Feron, L. / Fillery, S. / Gleave, E.S. / Goldberg, F.W. / Harlfinger, S. / Hanson, L. / Howard, M. / Howells, R. / Jackson, A. / Kemmitt, P. / Kingston, J.K. / Lamont, S. / Lewis, H.J. / Li, S. / Liu, L. / Ogg, D. / Phillips, C. / Polanski, R. / Robb, G. / Robinson, D. / Ross, S. / Smith, J.M. / Tonge, M. / Whiteley, R. / Yang, J. / Zhang, L. / Zhao, X. | ||||||
History |
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-Structure visualization
Structure viewer | Molecule: MolmilJmol/JSmol |
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-Downloads & links
-Download
PDBx/mmCIF format | 6t5v.cif.gz | 58.1 KB | Display | PDBx/mmCIF format |
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PDB format | pdb6t5v.ent.gz | 39.7 KB | Display | PDB format |
PDBx/mmJSON format | 6t5v.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/t5/6t5v ftp://data.pdbj.org/pub/pdb/validation_reports/t5/6t5v | HTTPS FTP |
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-Related 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: 19295.734 Da / Num. of mol.: 1 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 |
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#2: Chemical | ChemComp-MG / |
#3: Chemical | ChemComp-GDP / |
#4: Chemical | ChemComp-MKZ / |
#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: 2.42 Å3/Da / Density % sol: 49.07 % |
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Crystal grow | Temperature: 293 K / Method: vapor diffusion, sitting drop / Details: 50mM HEPES 100mM NaCl 2mM MgSO4 / PH range: 7.2 |
-Data collection
Diffraction | Mean temperature: 100 K / Serial crystal experiment: N |
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Diffraction source | Source: SYNCHROTRON / Site: Diamond / Beamline: I03 / Wavelength: 0.97625 Å |
Detector | Type: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Oct 9, 2015 |
Radiation | Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray |
Radiation wavelength | Wavelength: 0.97625 Å / Relative weight: 1 |
Reflection | Resolution: 1.31→45.09 Å / Num. obs: 45042 / % possible obs: 98.7 % / Redundancy: 5.6 % / Biso Wilson estimate: 14.5 Å2 / Rmerge(I) obs: 0.047 / Net I/σ(I): 20.9 |
Reflection shell | Resolution: 1.32→1.35 Å / Redundancy: 2.5 % / Rmerge(I) obs: 0.59 / Mean I/σ(I) obs: 2.4 / Num. unique obs: 2878 / % possible all: 88.3 |
-Processing
Software |
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Refinement | Method to determine structure: MOLECULAR REPLACEMENT Starting model: in house structure Resolution: 1.31→45.09 Å / Cor.coef. Fo:Fc: 0.9606 / Cor.coef. Fo:Fc free: 0.9576 / SU R Cruickshank DPI: 0.047 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.05 / SU Rfree Blow DPI: 0.053 / SU Rfree Cruickshank DPI: 0.051
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Displacement parameters | Biso max: 128.52 Å2 / Biso mean: 20.31 Å2 / Biso min: 7.8 Å2
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Refine analyze | Luzzati coordinate error obs: 0.165 Å | ||||||||||||||||||||||||||||||||||||||||
Refinement step | Cycle: final / Resolution: 1.31→45.09 Å
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LS refinement shell | Resolution: 1.31→1.34 Å / Rfactor Rfree error: 0
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Refinement TLS params. | Method: refined / Origin x: -18.2141 Å / Origin y: 1.5105 Å / Origin z: -12.3391 Å
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Refinement TLS group | Selection details: { B|* } |