[English] 日本語
Yorodumi- EMDB-18657: PROTAC-mediated complex of KRAS with VHL/Elongin-B/Elongin-C/Cull... -
+Open data
-Basic information
Entry | Database: EMDB / ID: EMD-18657 | |||||||||
---|---|---|---|---|---|---|---|---|---|---|
Title | PROTAC-mediated complex of KRAS with VHL/Elongin-B/Elongin-C/Cullin-2/Rbx1 | |||||||||
Map data | sharpened by deepemhancer | |||||||||
Sample |
| |||||||||
Keywords | TARGETED PROTEIN DEGRADATION / PROTAC / GTPASE / TRANSFERASE | |||||||||
Function / homology | Function and homology information regulation of cellular response to hypoxia / cullin-RING-type E3 NEDD8 transferase / cellular response to chemical stress / NEDD8 transferase activity / cullin-RING ubiquitin ligase complex / RHOBTB3 ATPase cycle / negative regulation of receptor signaling pathway via JAK-STAT / 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 / cellular response to chemical stress / NEDD8 transferase activity / cullin-RING ubiquitin ligase complex / RHOBTB3 ATPase cycle / negative regulation of receptor signaling pathway via JAK-STAT / 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 / elongin complex / VCB complex / positive regulation of protein autoubiquitination / protein neddylation / Replication of the SARS-CoV-1 genome / NEDD8 ligase activity / Cul5-RING ubiquitin ligase complex / negative regulation of response to oxidative stress / forebrain astrocyte development / ubiquitin-ubiquitin ligase activity / SCF ubiquitin ligase complex / Cul2-RING ubiquitin ligase complex / Cul4A-RING E3 ubiquitin ligase complex / intracellular non-membrane-bounded organelle / negative regulation of epithelial cell differentiation / negative regulation of type I interferon production / regulation of synaptic transmission, GABAergic / ubiquitin ligase complex scaffold activity / SCF-dependent proteasomal ubiquitin-dependent protein catabolic process / Cul4B-RING E3 ubiquitin ligase complex / Cul3-RING ubiquitin ligase complex / epithelial tube branching involved in lung morphogenesis / type I pneumocyte differentiation / SUMOylation of ubiquitinylation proteins / Rac protein signal transduction / Prolactin receptor signaling / positive regulation of Rac protein signal transduction / negative regulation of transcription elongation by RNA polymerase II / skeletal muscle cell differentiation / protein monoubiquitination / 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 / cullin family protein binding / 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 / protein K48-linked ubiquitination / 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 / Nuclear events stimulated by ALK signaling in cancer / 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 Similarity search - Function | |||||||||
Biological species | Homo sapiens (human) | |||||||||
Method | single particle reconstruction / cryo EM / Resolution: 3.5 Å | |||||||||
Authors | Fischer G / Peter D / Arce-Solano S | |||||||||
Funding support | Austria, 1 items
| |||||||||
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 / 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 |
|
-Structure visualization
Supplemental images |
---|
-Downloads & links
-EMDB archive
Map data | emd_18657.map.gz | 189 MB | EMDB map data format | |
---|---|---|---|---|
Header (meta data) | emd-18657-v30.xml emd-18657.xml | 32.9 KB 32.9 KB | Display Display | EMDB header |
FSC (resolution estimation) | emd_18657_fsc.xml | 14.4 KB | Display | FSC data file |
Images | emd_18657.png | 98.1 KB | ||
Filedesc metadata | emd-18657.cif.gz | 8.2 KB | ||
Others | emd_18657_additional_1.map.gz emd_18657_half_map_1.map.gz emd_18657_half_map_2.map.gz | 201.4 MB 3.3 MB 3.3 MB | ||
Archive directory | http://ftp.pdbj.org/pub/emdb/structures/EMD-18657 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-18657 | HTTPS FTP |
-Validation report
Summary document | emd_18657_validation.pdf.gz | 444.3 KB | Display | EMDB validaton report |
---|---|---|---|---|
Full document | emd_18657_full_validation.pdf.gz | 443.8 KB | Display | |
Data in XML | emd_18657_validation.xml.gz | 21.6 KB | Display | |
Data in CIF | emd_18657_validation.cif.gz | 28.3 KB | Display | |
Arichive directory | https://ftp.pdbj.org/pub/emdb/validation_reports/EMD-18657 ftp://ftp.pdbj.org/pub/emdb/validation_reports/EMD-18657 | HTTPS FTP |
-Related structure data
Related structure data | 8qu8M M: atomic model generated by this map |
---|---|
Similar structure data | Similarity search - Function & homologyF&H Search |
-Links
EMDB pages | EMDB (EBI/PDBe) / EMDataResource |
---|---|
Related items in Molecule of the Month |
-Map
File | Download / File: emd_18657.map.gz / Format: CCP4 / Size: 216 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES) | ||||||||||||||||||||||||||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Annotation | sharpened by deepemhancer | ||||||||||||||||||||||||||||||||||||
Projections & slices | Image control
Images are generated by Spider. | ||||||||||||||||||||||||||||||||||||
Voxel size | X=Y=Z: 0.99333 Å | ||||||||||||||||||||||||||||||||||||
Density |
| ||||||||||||||||||||||||||||||||||||
Symmetry | Space group: 1 | ||||||||||||||||||||||||||||||||||||
Details | EMDB XML:
|
-Supplemental data
-Additional map: unsharpened map from 3D flex
File | emd_18657_additional_1.map | ||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Annotation | unsharpened map from 3D flex | ||||||||||||
Projections & Slices |
| ||||||||||||
Density Histograms |
-Half map: half map B
File | emd_18657_half_map_1.map | ||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Annotation | half map B | ||||||||||||
Projections & Slices |
| ||||||||||||
Density Histograms |
-Half map: half map A
File | emd_18657_half_map_2.map | ||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Annotation | half map A | ||||||||||||
Projections & Slices |
| ||||||||||||
Density Histograms |
-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 |
---|---|
Processing | single particle reconstruction |
Aggregation state | particle |
-Sample preparation
Concentration | 0.916 mg/mL | ||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|
Buffer | pH: 7.5 Component:
| ||||||||||
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 |
-Electron microscopy
Microscope | FEI TITAN KRIOS |
---|---|
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: FIELD EMISSION GUN |
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 |