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- PDB-8qu8: PROTAC-mediated complex of KRAS with VHL/Elongin-B/Elongin-C/Cull... -

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Basic information

Entry
Database: PDB / ID: 8qu8
TitlePROTAC-mediated complex of KRAS with VHL/Elongin-B/Elongin-C/Cullin-2/Rbx1
Components
  • Cullin-2
  • E3 ubiquitin-protein ligase RBX1, N-terminally processed
  • Elongin-B
  • Elongin-C
  • GTPase KRas
  • von Hippel-Lindau disease tumor suppressor
KeywordsTRANSFERASE / TARGETED PROTEIN DEGRADATION / PROTAC / GTPASE
Function / homology
Function and homology information


regulation of cellular response to hypoxia / negative regulation of receptor signaling pathway via JAK-STAT / RHOBTB3 ATPase cycle / negative regulation of beige fat cell differentiation / cullin-RING-type E3 NEDD8 transferase / NEDD8 transferase activity / negative regulation of mitophagy / cullin-RING ubiquitin ligase complex / regulation of xenophagy / target-directed miRNA degradation ...regulation of cellular response to hypoxia / negative regulation of receptor signaling pathway via JAK-STAT / RHOBTB3 ATPase cycle / negative regulation of beige fat cell differentiation / cullin-RING-type E3 NEDD8 transferase / NEDD8 transferase activity / negative regulation of mitophagy / cullin-RING ubiquitin ligase complex / regulation of xenophagy / target-directed miRNA degradation / Loss of Function of FBXW7 in Cancer and NOTCH1 Signaling / cellular response to chemical stress / Cul7-RING ubiquitin ligase complex / elongin complex / regulation of cell cycle process / neural crest cell differentiation / Replication of the SARS-CoV-1 genome / RNA polymerase II transcription initiation surveillance / positive regulation of protein autoubiquitination / protein neddylation / transcription elongation factor activity / regulation of BMP signaling pathway / NEDD8 ligase activity / regulation of mitophagy / negative regulation of response to oxidative stress / regulation of centrosome duplication / protein K27-linked ubiquitination / VCB complex / Cul5-RING ubiquitin ligase complex / regulation of TOR signaling / ubiquitin-ubiquitin ligase activity / ubiquitin-dependent protein catabolic process via the C-end degron rule pathway / response to mineralocorticoid / GMP binding / SUMOylation of ubiquitinylation proteins / Cul2-RING ubiquitin ligase complex / SCF ubiquitin ligase complex / negative regulation of DNA-templated DNA replication / regulation of mitotic cytokinesis / Cul3-RING ubiquitin ligase complex / regulation of DNA damage checkpoint / LRR domain binding / negative regulation of transcription elongation by RNA polymerase II / negative regulation of type I interferon production / regulation of miRNA-mediated gene silencing / regulation of natural killer cell activation / SCF-dependent proteasomal ubiquitin-dependent protein catabolic process / response to isolation stress / Prolactin receptor signaling / regulation of cell cycle phase transition / Cul4A-RING E3 ubiquitin ligase complex / Cul4-RING E3 ubiquitin ligase complex / regulation of stem cell population maintenance / response to gravity / Cul4B-RING E3 ubiquitin ligase complex / myoblast proliferation / ubiquitin ligase complex scaffold activity / negative regulation of adipose tissue development / cardiac muscle cell proliferation / regulation of cellular response to stress / Pausing and recovery of Tat-mediated HIV elongation / Tat-mediated HIV elongation arrest and recovery / Signaling by RAS GAP mutants / Signaling by RAS GTPase mutants / Activation of RAS in B cells / limb development / HIV elongation arrest and recovery / Pausing and recovery of HIV elongation / RAS signaling downstream of NF1 loss-of-function variants / RUNX3 regulates p14-ARF / protein monoubiquitination / negative regulation of signal transduction / SOS-mediated signalling / cullin family protein binding / 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 / regulation of DNA-templated DNA replication initiation / centrosome duplication / SHC-related events triggered by IGF1R / Activated NTRK2 signals through FRS2 and FRS3 / Formation of HIV elongation complex in the absence of HIV Tat / cell morphogenesis / Estrogen-stimulated signaling through PRKCZ / SHC-mediated cascade:FGFR3 / MET activates RAS signaling / cilium assembly / positive regulation of Ras protein signal transduction / SHC-mediated cascade:FGFR2 / SHC-mediated cascade:FGFR4 / ubiquitin-like ligase-substrate adaptor activity / RNA Polymerase II Transcription Elongation / Signaling by PDGFRA transmembrane, juxtamembrane and kinase domain mutants / Signaling by PDGFRA extracellular domain mutants / PTK6 Regulates RHO GTPases, RAS GTPase and MAP kinases / Erythropoietin activates RAS / SHC-mediated cascade:FGFR1
Similarity search - Function
von Hippel-Lindau disease tumour suppressor, beta/alpha domain / von Hippel-Lindau disease tumour suppressor, alpha domain / von Hippel-Lindau disease tumour suppressor, beta domain / VHL superfamily / von Hippel-Lindau disease tumour suppressor, alpha domain superfamily / von Hippel-Lindau disease tumour suppressor, beta domain superfamily / VHL beta domain / VHL box domain / Zinc finger, RING-H2-type / RING-H2 zinc finger domain ...von Hippel-Lindau disease tumour suppressor, beta/alpha domain / von Hippel-Lindau disease tumour suppressor, alpha domain / von Hippel-Lindau disease tumour suppressor, beta domain / VHL superfamily / von Hippel-Lindau disease tumour suppressor, alpha domain superfamily / von Hippel-Lindau disease tumour suppressor, beta domain superfamily / VHL beta domain / VHL box domain / Zinc finger, RING-H2-type / RING-H2 zinc finger domain / Elongin-C / Elongin B / : / Cullin protein neddylation domain / Cullin, conserved site / Cullin family signature. / Cullin, N-terminal / Cullin repeat-like-containing domain superfamily / Cullin protein, neddylation domain / Cullin / Cullin protein neddylation domain / Cullin alpha solenoid domain / Cullin / : / Cullin alpha+beta domain / Cullin homology domain / Cullin homology domain superfamily / Cullin family profile. / S-phase kinase-associated protein 1-like / SKP1 component, POZ domain / Skp1 family, tetramerisation domain / Found in Skp1 protein family / Small GTPase, Ras-type / Small GTPase Ras domain profile. / Ran (Ras-related nuclear proteins) /TC4 subfamily of small GTPases / SKP1/BTB/POZ domain superfamily / Rho (Ras homology) subfamily of Ras-like small GTPases / Ras subfamily of RAS small GTPases / Small GTPase / Ras family / Rab subfamily of small GTPases / Zinc finger RING-type profile. / Zinc finger, RING-type / Small GTP-binding protein domain / Ubiquitin family / Ubiquitin homologues / Ubiquitin domain profile. / Ubiquitin-like domain / Zinc finger, RING/FYVE/PHD-type / Ubiquitin-like domain superfamily / Winged helix DNA-binding domain superfamily / Winged helix-like DNA-binding domain superfamily / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
GUANOSINE-5'-DIPHOSPHATE / Chem-WYL / GTPase KRas / von Hippel-Lindau disease tumor suppressor / E3 ubiquitin-protein ligase RBX1 / Cullin-2 / Elongin-C / Elongin-B
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.5 Å
AuthorsFischer, G. / Peter, D. / Arce-Solano, S.
Funding support Austria, 1items
OrganizationGrant numberCountry
Other privateBoehringer Ingelheim Austria
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
DepositionOct 14, 2023Deposition site: PDBE / Processing site: PDBE
Revision 1.0Dec 6, 2023Provider: repository / Type: Initial release
Revision 1.1Jan 24, 2024Group: Experimental preparation / Refinement description / Category: em_3d_fitting_list / em_buffer_component / Item: _em_buffer_component.concentration
Revision 1.2Sep 11, 2024Group: Data collection / Database references / Category: citation / citation_author / em_admin / Item: _em_admin.last_update
Revision 1.3Oct 2, 2024Group: Data collection / Database references / Category: citation / citation_author / em_admin
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.name / _em_admin.last_update

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: von Hippel-Lindau disease tumor suppressor
B: Elongin-B
C: Elongin-C
D: Cullin-2
E: E3 ubiquitin-protein ligase RBX1, N-terminally processed
F: GTPase KRas
hetero molecules


Theoretical massNumber of molelcules
Total (without water)169,49510
Polymers167,9016
Non-polymers1,5934
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area11760 Å2
ΔGint-77 kcal/mol
Surface area74930 Å2
MethodPISA

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Components

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Protein , 6 types, 6 molecules ABCDEF

#1: Protein von Hippel-Lindau disease tumor suppressor


Mass: 24049.545 Da / Num. of mol.: 1
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
#2: Protein Elongin-B / EloB / Elongin 18 kDa subunit / RNA polymerase II transcription factor SIII subunit B / SIII p18 / ...EloB / Elongin 18 kDa subunit / RNA polymerase II transcription factor SIII subunit B / SIII p18 / Transcription elongation factor B polypeptide 2


Mass: 13016.586 Da / Num. of mol.: 1
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
#3: Protein Elongin-C / EloC / Elongin 15 kDa subunit / RNA polymerase II transcription factor SIII subunit C / SIII p15 / ...EloC / Elongin 15 kDa subunit / RNA polymerase II transcription factor SIII subunit C / SIII p15 / Transcription elongation factor B polypeptide 1


Mass: 12353.939 Da / Num. of mol.: 1
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
#4: Protein Cullin-2 / CUL-2


Mass: 86967.734 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CUL2 / Production host: Escherichia coli (E. coli) / References: UniProt: Q13617
#5: Protein E3 ubiquitin-protein ligase RBX1, N-terminally processed / E3 ubiquitin-protein transferase RBX1 / N-terminally processed


Mass: 12158.780 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: RBX1, RNF75, ROC1 / Production host: Escherichia coli (E. coli) / References: UniProt: P62877
#6: Protein GTPase KRas / K-Ras 2 / Ki-Ras / c-K-ras / c-Ki-ras


Mass: 19354.824 Da / Num. of mol.: 1
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 , 3 types, 4 molecules

#7: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Zn
#8: Chemical ChemComp-GDP / GUANOSINE-5'-DIPHOSPHATE


Type: RNA linking / Mass: 443.201 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C10H15N5O11P2 / Comment: GDP, energy-carrying molecule*YM
#9: Chemical ChemComp-WYL / (2S,4R)-1-[(2S)-2-[4-[4-[(3S)-4-[4-[5-[(4S)-2-azanyl-3-cyano-4-methyl-6,7-dihydro-5H-1-benzothiophen-4-yl]-1,2,4-oxadiazol-3-yl]pyrimidin-2-yl]-3-methyl-1,4-diazepan-1-yl]butoxy]-1,2,3-triazol-1-yl]-3-methyl-butanoyl]-N-[(1R)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]-2-oxidanyl-ethyl]-4-oxidanyl-pyrrolidine-2-carboxamide


Mass: 1019.247 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C50H62N14O6S2 / Feature type: SUBJECT OF INVESTIGATION

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Details

Has ligand of interestY

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: KRAS/ACBI3/VHL/EloB/EloC/Cul2/Rbx1 / Type: COMPLEX
Details: PROTAC-mediated complex of KRAS with VHL/Elongin-B/Elongin-C/Cullin-2/Rbx1
Entity ID: #1-#6 / Source: RECOMBINANT
Molecular weightValue: 0.168 MDa / Experimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Escherichia coli (E. coli)
Buffer solutionpH: 7.5
Buffer component
IDConc.FormulaBuffer-ID
150 mMTRIS1
2100 mMNaCl1
30.5 mMTCEP1
42.0 mMMgCl21
SpecimenConc.: 0.916 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: COPPER / Grid mesh size: 200 divisions/in. / Grid type: Quantifoil R1.2/1.3
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 95 % / Chamber temperature: 4 K

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal magnification: 165000 X / Nominal defocus max: 2000 nm / Nominal defocus min: 800 nm / Cs: 2.7 mm
Specimen holderSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingElectron dose: 40 e/Å2 / Film or detector model: FEI FALCON IV (4k x 4k) / Num. of grids imaged: 1 / Num. of real images: 7634
EM imaging opticsEnergyfilter name: TFS Selectris / Energyfilter slit width: 10 eV

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Processing

EM software
IDNameVersionCategoryDetails (eV)
1cryoSPARC3particle selection
2EPUimage acquisition
4cryoSPARC3CTF correction
7Cootmodel fitting
9cryoSPARC3initial Euler assignment
10cryoSPARC3final Euler assignment
11cryoSPARC3classification
12cryoSPARC43D reconstruction3Dflex reconstruction
13PHENIXmodel refinement
CTF correctionType: NONE
Particle selectionNum. of particles selected: 2414442 / Details: before 2D classification
3D reconstructionResolution: 3.5 Å / Resolution method: OTHER / Num. of particles: 217000 / Details: cryoSPARC 3Dflex reconstruction / Symmetry type: POINT
Atomic model buildingPDB-ID: 5n4w

5n4w


Accession code: 5n4w / Details: KRAS-structure / Source name: PDB / Type: experimental model
RefinementHighest resolution: 3.5 Å

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