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Yorodumi- PDB-8afd: CRYSTAL STRUCTURE OF BIT-BLOCKED KRAS-G12V-S39C IN COMPLEX WITH C... -
+Open data
-Basic information
Entry | Database: PDB / ID: 8afd | |||||||||
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Title | CRYSTAL STRUCTURE OF BIT-BLOCKED KRAS-G12V-S39C IN COMPLEX WITH COMPOUND 20a | |||||||||
Components | GTPase KRas | |||||||||
Keywords | ONCOPROTEIN / KRAS / GTPase / G12C / Complex / Inhibitor | |||||||||
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 / positive regulation of Rac protein signal transduction / skeletal muscle cell differentiation / 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 / positive regulation of Rac protein signal transduction / skeletal muscle cell differentiation / 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 / SHC-related events triggered by IGF1R / glial cell proliferation / Activated NTRK2 signals through FRS2 and FRS3 / Estrogen-stimulated signaling through PRKCZ / 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 / positive regulation of glial cell proliferation / 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 / FRS-mediated FGFR4 signaling / Signaling by FGFR3 in disease / p38MAPK events / Tie2 Signaling / FRS-mediated FGFR1 signaling / striated muscle cell differentiation / Signaling by FGFR2 in disease / 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 / CD209 (DC-SIGN) signaling / NCAM signaling for neurite out-growth / SHC1 events in ERBB2 signaling / Downstream signal transduction / Constitutive Signaling by Overexpressed ERBB2 / Insulin receptor signalling cascade / Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants / small monomeric GTPase / G protein activity / VEGFR2 mediated cell proliferation / FCERI mediated MAPK activation / Signaling by ERBB2 TMD/JMD mutants / RAF activation / Signaling by high-kinase activity BRAF mutants / Constitutive Signaling by EGFRvIII / regulation of long-term neuronal synaptic plasticity / MAP2K and MAPK activation / visual learning / Signaling by ERBB2 ECD mutants / Signaling by SCF-KIT / Signaling by ERBB2 KD Mutants / 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 / 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 / negative regulation of neuron apoptotic process / Ras protein signal transduction / 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: 1.633 Å | |||||||||
Authors | Boettcher, J. / Kessler, D. | |||||||||
Funding support | Austria, 1items
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Citation | Journal: J.Med.Chem. / Year: 2022 Title: Fragment Optimization of Reversible Binding to the Switch II Pocket on KRAS Leads to a Potent, In Vivo Active KRAS G12C Inhibitor. Authors: Broker, J. / Waterson, A.G. / Smethurst, C. / Kessler, D. / Bottcher, J. / Mayer, M. / Gmaschitz, G. / Phan, J. / Little, A. / Abbott, J.R. / Sun, Q. / Gmachl, M. / Rudolph, D. / Arnhof, H. ...Authors: Broker, J. / Waterson, A.G. / Smethurst, C. / Kessler, D. / Bottcher, J. / Mayer, M. / Gmaschitz, G. / Phan, J. / Little, A. / Abbott, J.R. / Sun, Q. / Gmachl, M. / Rudolph, D. / Arnhof, H. / Rumpel, K. / Savarese, F. / Gerstberger, T. / Mischerikow, N. / Treu, M. / Herdeis, L. / Wunberg, T. / Gollner, A. / Weinstabl, H. / Mantoulidis, A. / Kramer, O. / McConnell, D.B. / W Fesik, S. | |||||||||
History |
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-Structure visualization
Structure viewer | Molecule: MolmilJmol/JSmol |
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-Downloads & links
-Download
PDBx/mmCIF format | 8afd.cif.gz | 402.9 KB | Display | PDBx/mmCIF format |
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PDB format | pdb8afd.ent.gz | 339.3 KB | Display | PDB format |
PDBx/mmJSON format | 8afd.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Summary document | 8afd_validation.pdf.gz | 2.5 MB | Display | wwPDB validaton report |
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Full document | 8afd_full_validation.pdf.gz | 2.5 MB | Display | |
Data in XML | 8afd_validation.xml.gz | 29.4 KB | Display | |
Data in CIF | 8afd_validation.cif.gz | 41.8 KB | Display | |
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/af/8afd ftp://data.pdbj.org/pub/pdb/validation_reports/af/8afd | HTTPS FTP |
-Related structure data
Related structure data | 7u8hC 8afbC 8afcC 7u90 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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2 |
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3 |
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4 |
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Unit cell |
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-Components
-Protein , 1 types, 4 molecules ABCD
#1: Protein | Mass: 19370.891 Da / Num. of mol.: 4 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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-Non-polymers , 5 types, 408 molecules
#2: Chemical | ChemComp-GDP / #3: Chemical | ChemComp-2XO / #4: Chemical | ChemComp-MG / #5: Chemical | #6: Water | ChemComp-HOH / | |
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-Details
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 | Density Matthews: 2.24 Å3/Da / Density % sol: 44.99 % |
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Crystal grow | Temperature: 297 K / Method: vapor diffusion / Details: 100mM PCB pH 5.9, 20% PEG 1500 |
-Data collection
Diffraction | Mean temperature: 100 K / Serial crystal experiment: N |
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Diffraction source | Source: SYNCHROTRON / Site: SLS / Beamline: X06SA / Wavelength: 0.999882 Å |
Detector | Type: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Feb 25, 2022 |
Radiation | Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray |
Radiation wavelength | Wavelength: 0.999882 Å / Relative weight: 1 |
Reflection | Resolution: 1.633→74.058 Å / Num. obs: 47959 / % possible obs: 55.7 % / Redundancy: 12.6 % / Biso Wilson estimate: 23.05 Å2 / Rmerge(I) obs: 0.118 / Rsym value: 0.118 / Net I/σ(I): 12.1 |
Reflection shell | Resolution: 1.633→1.853 Å / Redundancy: 9.4 % / Rmerge(I) obs: 1.187 / Mean I/σ(I) obs: 1.8 / Num. unique obs: 2399 / Rsym value: 1.187 / % possible all: 8.9 |
-Processing
Software |
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Refinement | Method to determine structure: MOLECULAR REPLACEMENT Starting model: 7U90 7u90 Resolution: 1.633→32.56 Å / Cor.coef. Fo:Fc: 0.906 / Cor.coef. Fo:Fc free: 0.896 / SU R Cruickshank DPI: 0.563 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.229 / SU Rfree Blow DPI: 0.184 / SU Rfree Cruickshank DPI: 0.182 Details: HYDROGENS WERE FULLY REFINED WITH ZERO OCCUPANCY AT NUCLEAR POSITION. REFINEMENT NOTES. NUMBER OF REFINEMENT NOTES : 1 NOTE 1 : IDEAL-DIST CONTACT TERM CONTACT SETUP. ALL ATOMS HAVE CCP4 ATOM TYPE FROM LIBRARY
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Displacement parameters | Biso max: 77.58 Å2 / Biso mean: 29.35 Å2 / Biso min: 10.22 Å2
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Refine analyze | Luzzati coordinate error obs: 0.31 Å | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Refinement step | Cycle: final / Resolution: 1.633→32.56 Å
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Refine LS restraints |
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LS refinement shell | Resolution: 1.633→1.79 Å / Rfactor Rfree error: 0
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