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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 / target-directed miRNA degradation / transcription elongation factor activity / 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 / target-directed miRNA degradation / transcription elongation factor activity / elongin complex / VCB complex / Replication of the SARS-CoV-1 genome / Cul5-RING ubiquitin ligase complex / forebrain astrocyte development / Cul2-RING ubiquitin ligase complex / intracellular non-membrane-bounded organelle / negative regulation of epithelial cell differentiation / regulation of synaptic transmission, GABAergic / epithelial tube branching involved in lung morphogenesis / type I pneumocyte differentiation / SUMOylation of ubiquitinylation proteins / Rac protein signal transduction / positive regulation of Rac protein signal transduction / negative regulation of transcription elongation by RNA polymerase II / skeletal muscle cell differentiation / 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 / HIV elongation arrest and recovery / Pausing and recovery of HIV elongation / RUNX3 regulates p14-ARF / SOS-mediated signalling / Activated NTRK3 signals through RAS / Activated NTRK2 signals through RAS / SHC1 events in ERBB4 signaling / ubiquitin-like ligase-substrate adaptor activity / Signalling to RAS / Tat-mediated elongation of the HIV-1 transcript / Formation of HIV-1 elongation complex containing HIV-1 Tat / SHC-related events triggered by IGF1R / glial cell proliferation / Activated NTRK2 signals through FRS2 and FRS3 / Formation of HIV elongation complex in the absence of HIV Tat / SHC-mediated cascade:FGFR2 / 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 / negative regulation of signal transduction / PTK6 Regulates RHO GTPases, RAS GTPase and MAP kinases / RNA Polymerase II Transcription Elongation / SHC-mediated cascade:FGFR4 / Signaling by FGFR4 in disease / Erythropoietin activates RAS / Signaling by CSF3 (G-CSF) / SHC-mediated cascade:FGFR1 / Formation of RNA Pol II elongation complex / FRS-mediated FGFR2 signaling / positive regulation of glial cell proliferation / protein-membrane adaptor activity / FRS-mediated FGFR3 signaling / Signaling by FLT3 ITD and TKD mutants / Signaling by FGFR2 in disease / FRS-mediated FGFR4 signaling / homeostasis of number of cells within a tissue / p38MAPK events / Signaling by FGFR3 in disease / Tie2 Signaling / negative regulation of TORC1 signaling / FRS-mediated FGFR1 signaling / striated muscle cell differentiation / RNA Polymerase II Pre-transcription Events / GRB2 events in EGFR signaling / FLT3 Signaling / SHC1 events in EGFR signaling / EGFR Transactivation by Gastrin / Signaling by FLT3 fusion proteins / 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 / negative regulation of autophagy / Constitutive Signaling by Overexpressed ERBB2 / Insulin receptor signalling cascade / Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants / transcription corepressor binding / small monomeric GTPase / VEGFR2 mediated cell proliferation / G protein activity / TP53 Regulates Transcription of DNA Repair Genes / transcription initiation at RNA polymerase II promoter / positive regulation of cell differentiation / FCERI mediated MAPK activation / transcription elongation by RNA polymerase II / Signaling by ERBB2 TMD/JMD mutants / RAF activation / 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: Science / Year: 2024 Title: Targeting cancer with small-molecule pan-KRAS degraders. Authors: Johannes Popow / William Farnaby / Andreas Gollner / Christiane Kofink / Gerhard Fischer / Melanie Wurm / David Zollman / Andre Wijaya / Nikolai Mischerikow / Carina Hasenoehrl / Polina ...Authors: Johannes Popow / William Farnaby / Andreas Gollner / Christiane Kofink / Gerhard Fischer / Melanie Wurm / David Zollman / Andre Wijaya / Nikolai Mischerikow / Carina Hasenoehrl / Polina Prokofeva / Heribert Arnhof / Silvia Arce-Solano / Sammy Bell / Georg Boeck / Emelyne Diers / Aileen B Frost / Jake Goodwin-Tindall / Jale Karolyi-Oezguer / Shakil Khan / Theresa Klawatsch / Manfred Koegl / Roland Kousek / Barbara Kratochvil / Katrin Kropatsch / Arnel A Lauber / Ross McLennan / Sabine Olt / Daniel Peter / Oliver Petermann / Vanessa Roessler / Peggy Stolt-Bergner / Patrick Strack / Eva Strauss / Nicole Trainor / Vesna Vetma / Claire Whitworth / Siying Zhong / Jens Quant / Harald Weinstabl / Bernhard Kuster / Peter Ettmayer / Alessio Ciulli / Abstract: Mutations in the Kirsten rat sarcoma viral oncogene homolog (KRAS) protein are highly prevalent in cancer. However, small-molecule concepts that address oncogenic KRAS alleles remain elusive beyond ...Mutations in the Kirsten rat sarcoma viral oncogene homolog (KRAS) protein are highly prevalent in cancer. However, small-molecule concepts that address oncogenic KRAS alleles remain elusive beyond replacing glycine at position 12 with cysteine (G12C), which is clinically drugged through covalent inhibitors. Guided by biophysical and structural studies of ternary complexes, we designed a heterobifunctional small molecule that potently degrades 13 out of 17 of the most prevalent oncogenic KRAS alleles. Compared with inhibition, KRAS degradation results in more profound and sustained pathway modulation across a broad range of KRAS mutant cell lines, killing cancer cells while sparing models without genetic KRAS aberrations. Pharmacological degradation of oncogenic KRAS was tolerated and led to tumor regression in vivo. Together, these findings unveil a new path toward addressing KRAS-driven cancers with small-molecule degraders. #1: 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 | 215 KB | Display | PDBx/mmCIF format |
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PDB format | pdb8qw7.ent.gz | 164 KB | Display | PDB format |
PDBx/mmJSON format | 8qw7.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Summary document | 8qw7_validation.pdf.gz | 1.6 MB | Display | wwPDB validaton report |
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Full document | 8qw7_full_validation.pdf.gz | 1.8 MB | Display | |
Data in XML | 8qw7_validation.xml.gz | 41.5 KB | Display | |
Data in CIF | 8qw7_validation.cif.gz | 55.2 KB | Display | |
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/qw/8qw7 ftp://data.pdbj.org/pub/pdb/validation_reports/qw/8qw7 | HTTPS FTP |
-Related structure data
Related structure data | 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
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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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