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- PDB-8qw6: Crystal Structure of compound 3 in complex with KRAS G12V C118S G... -

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Basic information

Entry
Database: PDB / ID: 8qw6
TitleCrystal Structure of compound 3 in complex with KRAS G12V C118S GDP and pVHL:ElonginC:ElonginB
Components
  • Elongin-B
  • Elongin-C
  • GTPase KRas
  • von Hippel-Lindau disease tumor suppressor
KeywordsONCOPROTEIN / Ternary Complex / PROTAC / Degrader / oncology
Function / homology
Function and homology information


regulation of cellular response to hypoxia / negative regulation of receptor signaling pathway via JAK-STAT / RHOBTB3 ATPase cycle / target-directed miRNA degradation / elongin complex / Replication of the SARS-CoV-1 genome / transcription elongation factor activity / VCB complex / Cul5-RING ubiquitin ligase complex / response to mineralocorticoid ...regulation of cellular response to hypoxia / negative regulation of receptor signaling pathway via JAK-STAT / RHOBTB3 ATPase cycle / target-directed miRNA degradation / elongin complex / Replication of the SARS-CoV-1 genome / transcription elongation factor activity / VCB complex / Cul5-RING ubiquitin ligase complex / response to mineralocorticoid / GMP binding / ubiquitin-dependent protein catabolic process via the C-end degron rule pathway / forebrain astrocyte development / Cul2-RING ubiquitin ligase complex / SUMOylation of ubiquitinylation proteins / LRR domain binding / regulation of synaptic transmission, GABAergic / negative regulation of epithelial cell differentiation / response to isolation stress / response to gravity / epithelial tube branching involved in lung morphogenesis / type I pneumocyte differentiation / Rac protein signal transduction / negative regulation of transcription elongation by RNA polymerase II / myoblast proliferation / 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 / HIV elongation arrest and recovery / Pausing and recovery of HIV elongation / RAS signaling downstream of NF1 loss-of-function variants / RUNX3 regulates p14-ARF / positive regulation of glial cell proliferation / skeletal muscle cell differentiation / SOS-mediated signalling / Activated NTRK3 signals through RAS / Activated NTRK2 signals through RAS / negative regulation of signal transduction / cardiac muscle cell proliferation / 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 / SHC-related events triggered by IGF1R / Activated NTRK2 signals through FRS2 and FRS3 / Estrogen-stimulated signaling through PRKCZ / positive regulation of Rac protein signal transduction / Formation of HIV elongation complex in the absence of HIV Tat / SHC-mediated cascade:FGFR3 / glial cell proliferation / MET activates RAS signaling / SHC-mediated cascade:FGFR2 / ubiquitin-like ligase-substrate adaptor activity / SHC-mediated cascade:FGFR4 / 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 / RNA Polymerase II Transcription Elongation / SHC-mediated cascade:FGFR1 / Signaling by FGFR4 in disease / Formation of RNA Pol II elongation complex / Signaling by CSF3 (G-CSF) / FRS-mediated FGFR3 signaling / Signaling by FLT3 ITD and TKD mutants / FRS-mediated FGFR2 signaling / FRS-mediated FGFR4 signaling / p38MAPK events / striated muscle cell differentiation / FRS-mediated FGFR1 signaling / Signaling by FGFR3 in disease / Tie2 Signaling / negative regulation of TORC1 signaling / protein-membrane adaptor activity / Signaling by FGFR2 in disease / RNA Polymerase II Pre-transcription Events / Signaling by FLT3 fusion proteins / GRB2 events in EGFR signaling / SHC1 events in EGFR signaling / FLT3 Signaling / Signaling by FGFR1 in disease / EGFR Transactivation by Gastrin / NCAM signaling for neurite out-growth / CD209 (DC-SIGN) signaling / Downstream signal transduction / GRB2 events in ERBB2 signaling / homeostasis of number of cells within a tissue / Insulin receptor signalling cascade / SHC1 events in ERBB2 signaling / ciliary tip / Constitutive Signaling by Overexpressed ERBB2 / response to glucocorticoid / Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants / Ras activation upon Ca2+ influx through NMDA receptor / transcription corepressor binding / negative regulation of autophagy / VEGFR2 mediated cell proliferation / protein serine/threonine kinase binding
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 / Elongin-C / Elongin B ...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 / Elongin-C / Elongin B / 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 / Small GTP-binding protein domain / Ubiquitin family / Ubiquitin homologues / Ubiquitin domain profile. / Ubiquitin-like domain / Ubiquitin-like domain superfamily / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
GUANOSINE-5'-DIPHOSPHATE / Chem-X4R / GTPase KRas / von Hippel-Lindau disease tumor suppressor / Elongin-C / Elongin-B
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.2 Å
AuthorsZollman, D. / Farnaby, W. / Ciulli, A.
Funding support United Kingdom, 1items
OrganizationGrant numberCountry
Other private United Kingdom
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 18, 2023Deposition site: PDBE / Processing site: PDBE
Revision 1.0Dec 6, 2023Provider: repository / Type: Initial release
Revision 1.1Sep 11, 2024Group: Database references / Category: citation / citation_author
Revision 1.2Oct 2, 2024Group: Database references / Category: citation / citation_author
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

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
H: Elongin-B
G: Elongin-C
F: von Hippel-Lindau disease tumor suppressor
E: GTPase KRas
D: Elongin-B
C: Elongin-C
B: von Hippel-Lindau disease tumor suppressor
A: GTPase KRas
hetero molecules


Theoretical massNumber of molelcules
Total (without water)124,45014
Polymers121,5608
Non-polymers2,8906
Water86548
1
H: Elongin-B
G: Elongin-C
F: von Hippel-Lindau disease tumor suppressor
E: GTPase KRas
hetero molecules


Theoretical massNumber of molelcules
Total (without water)62,2257
Polymers60,7804
Non-polymers1,4453
Water724
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
D: Elongin-B
C: Elongin-C
B: von Hippel-Lindau disease tumor suppressor
A: GTPase KRas
hetero molecules


Theoretical massNumber of molelcules
Total (without water)62,2257
Polymers60,7804
Non-polymers1,4453
Water543
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)70.207, 72.298, 80.794
Angle α, β, γ (deg.)112.250, 100.610, 100.570
Int Tables number1
Space group name H-MP1
Space group name HallP1
Symmetry operation#1: x,y,z

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Components

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Protein , 4 types, 8 molecules HDGCFBEA

#1: 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: 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 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: 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 von Hippel-Lindau disease tumor suppressor / Protein G7 / pVHL


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 GTPase KRas / K-Ras 2 / Ki-Ras / c-K-ras / c-Ki-ras


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, 54 molecules

#5: Chemical ChemComp-GDP / GUANOSINE-5'-DIPHOSPHATE


Type: RNA linking / Mass: 443.201 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C10H15N5O11P2 / Comment: GDP, energy-carrying molecule*YM
#6: Chemical ChemComp-X4R / (2S,4R)-1-[(2S)-2-[6-[(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]hexanoylamino]-3,3-dimethyl-butanoyl]-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]-4-oxidanyl-pyrrolidine-2-carboxamide


Mass: 977.251 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C50H64N12O5S2 / Feature type: SUBJECT OF INVESTIGATION
#7: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Mg
#8: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 48 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestY

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

CrystalDensity Matthews: 2.95 Å3/Da / Density % sol: 58.27 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 8.5
Details: 200 mM sodium citrate, 100 mM BIS-TRIS propane pH 8.5, 20% w/v polyethylene glycol 3350

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Data collection

DiffractionMean temperature: 80 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X10SA / Wavelength: 1.00002 Å
DetectorType: DECTRIS PILATUS 6M-F / Detector: PIXEL / Date: May 4, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.00002 Å / Relative weight: 1
ReflectionResolution: 2.2→66.3 Å / Num. obs: 39191 / % possible obs: 82.3 % / Redundancy: 2.5 % / Biso Wilson estimate: 42.98 Å2 / CC1/2: 1 / Rpim(I) all: 0.04 / Rrim(I) all: 0.024 / Net I/σ(I): 7.4
Reflection shellResolution: 2.21→2.455 Å / Num. unique obs: 1960 / Rpim(I) all: 0.331

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Processing

Software
NameVersionClassification
PHENIX1.20.1_4487refinement
PHENIX1.20.1_4487refinement
autoPROCdata reduction
autoPROCdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.2→46.37 Å / SU ML: 0.3396 / Cross valid method: FREE R-VALUE / σ(F): 1.99 / Phase error: 41.5685
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2949 2000 5.1 %
Rwork0.255 37180 -
obs0.257 39180 55.51 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 48.29 Å2
Refinement stepCycle: LAST / Resolution: 2.2→46.37 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7752 0 196 48 7996
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.02488122
X-RAY DIFFRACTIONf_angle_d2.056711049
X-RAY DIFFRACTIONf_chiral_restr0.13891244
X-RAY DIFFRACTIONf_plane_restr0.01461490
X-RAY DIFFRACTIONf_dihedral_angle_d17.3063092
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.2-2.250.510730.380555X-RAY DIFFRACTION1.16
2.25-2.310.4752120.4182224X-RAY DIFFRACTION4.73
2.31-2.380.3749300.392566X-RAY DIFFRACTION11.85
2.38-2.460.3985590.34761080X-RAY DIFFRACTION22.72
2.46-2.550.3503920.36221717X-RAY DIFFRACTION35.91
2.55-2.650.39041280.35022393X-RAY DIFFRACTION49.97
2.65-2.770.35151590.35892941X-RAY DIFFRACTION60.75
2.77-2.920.35311810.34413370X-RAY DIFFRACTION71.05
2.92-3.10.38522020.34433750X-RAY DIFFRACTION78.35
3.1-3.340.37992120.29293951X-RAY DIFFRACTION82.48
3.34-3.670.31242230.2644155X-RAY DIFFRACTION87
3.67-4.20.26872320.22134317X-RAY DIFFRACTION90.2
4.2-5.30.22712390.19384439X-RAY DIFFRACTION92.51
5.3-46.370.252280.22124222X-RAY DIFFRACTION88.17

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