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Yorodumi- PDB-8qw7: Crystal Structure of compound 4 in complex with KRAS G12V C118S G... -
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-Basic information
Entry | Database: PDB / ID: 8qw7 | ||||||
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Title | Crystal Structure of compound 4 in complex with KRAS G12V C118S GDP and pVHL:ElonginC:ElonginB | ||||||
Components |
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Keywords | ONCOPROTEIN / Ternary Complex / PROTAC / E3 ligase / oncology | ||||||
Function / homology | Function and homology information regulation of cellular response to hypoxia / RHOBTB3 ATPase cycle / negative regulation of receptor signaling pathway via JAK-STAT / transcription elongation factor activity / target-directed miRNA degradation / elongin complex / VCB complex / Replication of the SARS-CoV-1 genome / Cul5-RING ubiquitin ligase complex / forebrain astrocyte development ...regulation of cellular response to hypoxia / RHOBTB3 ATPase cycle / negative regulation of receptor signaling pathway via JAK-STAT / transcription elongation factor activity / target-directed miRNA degradation / elongin complex / VCB complex / Replication of the SARS-CoV-1 genome / Cul5-RING ubiquitin ligase complex / forebrain astrocyte development / Cul2-RING ubiquitin ligase complex / regulation of synaptic transmission, GABAergic / negative regulation of epithelial cell differentiation / epithelial tube branching involved in lung morphogenesis / type I pneumocyte differentiation / intracellular non-membrane-bounded organelle / Rac protein signal transduction / SUMOylation of ubiquitinylation proteins / negative regulation of transcription elongation by RNA polymerase II / 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 / Pausing and recovery of Tat-mediated HIV elongation / Tat-mediated HIV elongation arrest and recovery / RAS signaling downstream of NF1 loss-of-function variants / RUNX3 regulates p14-ARF / HIV elongation arrest and recovery / Pausing and recovery of HIV elongation / ubiquitin-like ligase-substrate adaptor activity / SOS-mediated signalling / Activated NTRK3 signals through RAS / Activated NTRK2 signals through RAS / SHC1 events in ERBB4 signaling / Signalling to RAS / Tat-mediated elongation of the HIV-1 transcript / Formation of HIV-1 elongation complex containing HIV-1 Tat / glial cell proliferation / SHC-related events triggered by IGF1R / Activated NTRK2 signals through FRS2 and FRS3 / Estrogen-stimulated signaling through PRKCZ / Formation of HIV elongation complex in the absence of HIV Tat / SHC-mediated cascade:FGFR3 / MET activates RAS signaling / PTK6 Regulates RHO GTPases, RAS GTPase and MAP kinases / negative regulation of signal transduction / Signaling by PDGFRA transmembrane, juxtamembrane and kinase domain mutants / Signaling by PDGFRA extracellular domain mutants / SHC-mediated cascade:FGFR2 / RNA Polymerase II Transcription Elongation / SHC-mediated cascade:FGFR4 / Signaling by FGFR4 in disease / SHC-mediated cascade:FGFR1 / Formation of RNA Pol II elongation complex / Erythropoietin activates RAS / protein-membrane adaptor activity / homeostasis of number of cells within a tissue / 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 / negative regulation of TORC1 signaling / FRS-mediated FGFR4 signaling / Signaling by FGFR3 in disease / FRS-mediated FGFR1 signaling / p38MAPK events / Tie2 Signaling / Signaling by FGFR2 in disease / RNA Polymerase II Pre-transcription Events / 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 / negative regulation of autophagy / small monomeric GTPase / G protein activity / transcription corepressor binding / Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants / VEGFR2 mediated cell proliferation / transcription elongation by RNA polymerase II / transcription initiation at RNA polymerase II promoter / positive regulation of cell differentiation / TP53 Regulates Transcription of DNA Repair Genes / FCERI mediated MAPK activation / regulation of long-term neuronal synaptic plasticity / Signaling by ERBB2 TMD/JMD mutants / Vif-mediated degradation of APOBEC3G Similarity search - Function | ||||||
Biological species | Homo sapiens (human) | ||||||
Method | X-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.36 Å | ||||||
Authors | Zollman, D. / Farnaby, W. / Ciulli, A. | ||||||
Funding support | United Kingdom, 1items
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Citation | Journal: Biorxiv / Year: 2023 Title: Targeting cancer with small molecule pan-KRAS degraders Authors: Popow, J. / Farnaby, W. / Gollner, A. / Kofink, C. / Fischer, G. / Wurm, M. / Zollman, D. / Wijaya, A. / Mischerikow, N. / Hasenoehrl, C. / Prokofeva, P. / Arnhof, H. / Arce-Solano, S. / ...Authors: Popow, J. / Farnaby, W. / Gollner, A. / Kofink, C. / Fischer, G. / Wurm, M. / Zollman, D. / Wijaya, A. / Mischerikow, N. / Hasenoehrl, C. / Prokofeva, P. / Arnhof, H. / Arce-Solano, S. / Bell, S. / Boeck, G. / Diers, E. / Frost, A. / Goodwin-Tindall, J. / Karolyi-Oezguer, J. / Khan, S. / Klawatsch, T. / Koegl, M. / Kousek, R. / Kratochvil, B. / Kropatsch, K. / Lauber, A. / McLennan, R. / Olt, S. / Peter, D. / Petermann, O. / Roessler, V. / Stolt-Bergner, P. / Strack, P. / Strauss, E. / Trainor, N. / Vetma, V. / Whitworth, C. / Zhong, S. / Quant, J. / Weinstabl, H. / Kuster, B. / Ettmayer, P. / Ciulli, A. | ||||||
History |
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-Structure visualization
Structure viewer | Molecule: MolmilJmol/JSmol |
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-Downloads & links
-Download
PDBx/mmCIF format | 8qw7.cif.gz | 214.6 KB | Display | PDBx/mmCIF format |
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PDB format | pdb8qw7.ent.gz | 163.9 KB | Display | PDB format |
PDBx/mmJSON format | 8qw7.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/qw/8qw7 ftp://data.pdbj.org/pub/pdb/validation_reports/qw/8qw7 | HTTPS FTP |
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-Related structure data
Related structure data | 8qu8C 8qugC 8qvuC 8qw6C 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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Unit cell |
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-Components
-Protein , 4 types, 8 molecules DHCGBFAE
#1: Protein | Mass: 11748.406 Da / Num. of mol.: 2 / Mutation: delta 105-118 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: ELOB, TCEB2 / Production host: Escherichia coli (E. coli) / References: UniProt: Q15370 #2: Protein | Mass: 10974.616 Da / Num. of mol.: 2 / Mutation: delta 1-16 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: ELOC, TCEB1 / Production host: Escherichia coli (E. coli) / References: UniProt: Q15369 #3: Protein | Mass: 18702.291 Da / Num. of mol.: 2 / Mutation: Delta 1-53 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: VHL / Production host: Escherichia coli (E. coli) / References: UniProt: P40337 #4: Protein | Mass: 19354.824 Da / Num. of mol.: 2 / Mutation: G12V, C118S 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 , 4 types, 29 molecules
#5: Chemical | #6: Chemical | #7: Chemical | #8: 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: 2.82 Å3/Da / Density % sol: 56.4 % |
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Crystal grow | Temperature: 277 K / Method: vapor diffusion, sitting drop / pH: 8.5 Details: 200 mM Lithium sulfate monohydrate, 100 mM BIS-TRIS propane pH 5.5, 25% w/v polyethylene glycol 3350 |
-Data collection
Diffraction | Mean temperature: 80 K / Serial crystal experiment: N |
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Diffraction source | Source: SYNCHROTRON / Site: SLS / Beamline: X10SA / Wavelength: 0.999891 Å |
Detector | Type: DECTRIS EIGER2 X 16M / Detector: PIXEL / Date: Feb 7, 2020 |
Radiation | Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray |
Radiation wavelength | Wavelength: 0.999891 Å / Relative weight: 1 |
Reflection | Resolution: 2.36→67.42 Å / Num. obs: 30823 / % possible obs: 92.8 % / Redundancy: 7 % / Biso Wilson estimate: 58.3 Å2 / Rpim(I) all: 0.032 / Net I/σ(I): 0.132 |
Reflection shell | Resolution: 2.412→2.698 Å / Num. unique obs: 1204 / Rpim(I) all: 0.453 |
-Processing
Software |
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Refinement | Method to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.36→67.42 Å / SU ML: 0.2993 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 39.8159 Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
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Solvent computation | Shrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Displacement parameters | Biso mean: 59.05 Å2 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Refinement step | Cycle: LAST / Resolution: 2.36→67.42 Å
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Refine LS restraints |
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LS refinement shell |
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