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- EMDB-18657: PROTAC-mediated complex of KRAS with VHL/Elongin-B/Elongin-C/Cull... -
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Open data
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Basic information
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Title | PROTAC-mediated complex of KRAS with VHL/Elongin-B/Elongin-C/Cullin-2/Rbx1 | |||||||||
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![]() | TARGETED PROTEIN DEGRADATION / PROTAC / GTPASE / TRANSFERASE | |||||||||
Function / homology | ![]() regulation of cellular response to hypoxia / cullin-RING-type E3 NEDD8 transferase / NEDD8 transferase activity / RHOBTB3 ATPase cycle / negative regulation of receptor signaling pathway via JAK-STAT / cullin-RING ubiquitin ligase complex / cellular response to chemical stress / Cul7-RING ubiquitin ligase complex / ubiquitin-dependent protein catabolic process via the C-end degron rule pathway / target-directed miRNA degradation ...regulation of cellular response to hypoxia / cullin-RING-type E3 NEDD8 transferase / NEDD8 transferase activity / RHOBTB3 ATPase cycle / negative regulation of receptor signaling pathway via JAK-STAT / cullin-RING ubiquitin ligase complex / cellular response to chemical stress / Cul7-RING ubiquitin ligase complex / ubiquitin-dependent protein catabolic process via the C-end degron rule pathway / target-directed miRNA degradation / Loss of Function of FBXW7 in Cancer and NOTCH1 Signaling / transcription elongation factor activity / VCB complex / elongin complex / positive regulation of protein autoubiquitination / protein neddylation / Replication of the SARS-CoV-1 genome / NEDD8 ligase activity / negative regulation of response to oxidative stress / Cul5-RING ubiquitin ligase complex / GMP binding / response to mineralocorticoid / SCF ubiquitin ligase complex / forebrain astrocyte development / Cul2-RING ubiquitin ligase complex / intracellular membraneless organelle / ubiquitin-ubiquitin ligase activity / negative regulation of type I interferon production / Cul4A-RING E3 ubiquitin ligase complex / LRR domain binding / SCF-dependent proteasomal ubiquitin-dependent protein catabolic process / Cul3-RING ubiquitin ligase complex / negative regulation of epithelial cell differentiation / Cul4B-RING E3 ubiquitin ligase complex / response to isolation stress / ubiquitin ligase complex scaffold activity / SUMOylation of ubiquitinylation proteins / negative regulation of mitophagy / response to gravity / type I pneumocyte differentiation / regulation of synaptic transmission, GABAergic / epithelial tube branching involved in lung morphogenesis / Prolactin receptor signaling / Rac protein signal transduction / positive regulation of Rac protein signal transduction / Signaling by RAS GAP mutants / Signaling by RAS GTPase mutants / Activation of RAS in B cells / cullin family protein binding / myoblast proliferation / skeletal muscle cell differentiation / Pausing and recovery of Tat-mediated HIV elongation / Tat-mediated HIV elongation arrest and recovery / RAS signaling downstream of NF1 loss-of-function variants / negative regulation of transcription elongation by RNA polymerase II / RUNX3 regulates p14-ARF / HIV elongation arrest and recovery / Pausing and recovery of HIV elongation / SOS-mediated signalling / Activated NTRK3 signals through RAS / Activated NTRK2 signals through RAS / SHC1 events in ERBB4 signaling / protein monoubiquitination / cardiac muscle cell proliferation / Signalling to RAS / Tat-mediated elongation of the HIV-1 transcript / ubiquitin-like ligase-substrate adaptor activity / Activated NTRK2 signals through FRS2 and FRS3 / negative regulation of signal transduction / SHC-related events triggered by IGF1R / Formation of HIV-1 elongation complex containing HIV-1 Tat / Estrogen-stimulated signaling through PRKCZ / glial cell proliferation / SHC-mediated cascade:FGFR3 / MET activates RAS signaling / Formation of HIV elongation complex in the absence of HIV Tat / protein K48-linked ubiquitination / SHC-mediated cascade:FGFR2 / 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:FGFR4 / Erythropoietin activates RAS / Signaling by FGFR4 in disease / SHC-mediated cascade:FGFR1 / RNA Polymerase II Transcription Elongation / Nuclear events stimulated by ALK signaling in cancer / Formation of RNA Pol II elongation complex / FRS-mediated FGFR3 signaling / Signaling by CSF3 (G-CSF) / Regulation of BACH1 activity / Signaling by FLT3 ITD and TKD mutants / FRS-mediated FGFR2 signaling / FRS-mediated FGFR4 signaling / protein-membrane adaptor activity / Signaling by FGFR3 in disease / p38MAPK events / FRS-mediated FGFR1 signaling / Tie2 Signaling / negative regulation of TORC1 signaling Similarity search - Function | |||||||||
Biological species | ![]() | |||||||||
Method | single particle reconstruction / cryo EM / Resolution: 3.5 Å | |||||||||
![]() | Fischer G / Peter D / Arce-Solano S | |||||||||
Funding support | ![]()
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![]() | ![]() 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: ![]() 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 / Bell S / Boeck G / Diers E / ...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
Supplemental images |
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Downloads & links
-EMDB archive
Map data | ![]() | 189 MB | ![]() | |
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Header (meta data) | ![]() ![]() | 32.9 KB 32.9 KB | Display Display | ![]() |
FSC (resolution estimation) | ![]() | 14.4 KB | Display | ![]() |
Images | ![]() | 98.1 KB | ||
Filedesc metadata | ![]() | 8.2 KB | ||
Others | ![]() ![]() ![]() | 201.4 MB 3.3 MB 3.3 MB | ||
Archive directory | ![]() ![]() | HTTPS FTP |
-Validation report
Summary document | ![]() | 444.3 KB | Display | ![]() |
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Full document | ![]() | 443.8 KB | Display | |
Data in XML | ![]() | 21.6 KB | Display | |
Data in CIF | ![]() | 28.3 KB | Display | |
Arichive directory | ![]() ![]() | HTTPS FTP |
-Related structure data
Related structure data | ![]() 8qu8M M: atomic model generated by this map |
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Similar structure data | Similarity search - Function & homology ![]() |
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Links
EMDB pages | ![]() ![]() |
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Related items in Molecule of the Month |
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Map
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Annotation | sharpened by deepemhancer | ||||||||||||||||||||||||||||||||||||
Projections & slices | Image control
Images are generated by Spider. | ||||||||||||||||||||||||||||||||||||
Voxel size | X=Y=Z: 0.99333 Å | ||||||||||||||||||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||||||||||||||||||
Details | EMDB XML:
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-Supplemental data
-Additional map: unsharpened map from 3D flex
File | emd_18657_additional_1.map | ||||||||||||
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Annotation | unsharpened map from 3D flex | ||||||||||||
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Density Histograms |
-Half map: half map B
File | emd_18657_half_map_1.map | ||||||||||||
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Annotation | half map B | ||||||||||||
Projections & Slices |
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Density Histograms |
-Half map: half map A
File | emd_18657_half_map_2.map | ||||||||||||
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Annotation | half map A | ||||||||||||
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Density Histograms |
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Sample components
+Entire : KRAS/ACBI3/VHL/EloB/EloC/Cul2/Rbx1
+Supramolecule #1: KRAS/ACBI3/VHL/EloB/EloC/Cul2/Rbx1
+Macromolecule #1: von Hippel-Lindau disease tumor suppressor
+Macromolecule #2: Elongin-B
+Macromolecule #3: Elongin-C
+Macromolecule #4: Cullin-2
+Macromolecule #5: E3 ubiquitin-protein ligase RBX1, N-terminally processed
+Macromolecule #6: GTPase KRas
+Macromolecule #7: ZINC ION
+Macromolecule #8: GUANOSINE-5'-DIPHOSPHATE
+Macromolecule #9: (2S,4R)-1-[(2S)-2-[4-[4-[(3S)-4-[4-[5-[(4S)-2-azanyl-3-cyano-4-me...
-Experimental details
-Structure determination
Method | cryo EM |
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![]() | single particle reconstruction |
Aggregation state | particle |
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Sample preparation
Concentration | 0.916 mg/mL | ||||||||||
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Buffer | pH: 7.5 Component:
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Grid | Model: Quantifoil R1.2/1.3 / Material: COPPER / Mesh: 200 / Support film - Material: CARBON / Support film - topology: HOLEY / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Time: 15 sec. / Pretreatment - Atmosphere: AIR | ||||||||||
Vitrification | Cryogen name: ETHANE / Chamber humidity: 95 % / Chamber temperature: 4 K / Instrument: FEI VITROBOT MARK IV |
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Electron microscopy
Microscope | FEI TITAN KRIOS |
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Specialist optics | Energy filter - Name: TFS Selectris / Energy filter - Slit width: 10 eV |
Image recording | Film or detector model: FEI FALCON IV (4k x 4k) / Number grids imaged: 1 / Number real images: 7634 / Average electron dose: 40.0 e/Å2 |
Electron beam | Acceleration voltage: 300 kV / Electron source: ![]() |
Electron optics | Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 2.0 µm / Nominal defocus min: 0.8 µm / Nominal magnification: 165000 |
Sample stage | Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER |
Experimental equipment | ![]() Model: Titan Krios / Image courtesy: FEI Company |