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- PDB-8qvu: Crystal Structure of ligand ACBI3 in complex with KRAS G12D C118S... -

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Entry
Database: PDB / ID: 8qvu
TitleCrystal Structure of ligand ACBI3 in complex with KRAS G12D C118S GDP and pVHL:ElonginC:ElonginB complex
Components
  • Elongin-B
  • Elongin-C
  • Isoform 2B of GTPase KRas
  • von Hippel-Lindau disease tumor suppressor
KeywordsGENE REGULATION / Ternary Complex / PROTAC / Degrader / E3 ligase / Ligase
Function / homology
Function and homology information


regulation of cellular response to hypoxia / negative regulation of receptor signaling pathway via JAK-STAT / RHOBTB3 ATPase cycle / transcription elongation factor activity / target-directed miRNA degradation / elongin complex / Replication of the SARS-CoV-1 genome / 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 / transcription elongation factor activity / target-directed miRNA degradation / elongin complex / Replication of the SARS-CoV-1 genome / VCB complex / Cul5-RING ubiquitin ligase complex / response to mineralocorticoid / GMP binding / intracellular membraneless organelle / forebrain astrocyte development / ubiquitin-dependent protein catabolic process via the C-end degron rule pathway / LRR domain binding / Cul2-RING ubiquitin ligase complex / regulation of synaptic transmission, GABAergic / negative regulation of epithelial cell differentiation / response to isolation stress / SUMOylation of ubiquitinylation proteins / response to gravity / epithelial tube branching involved in lung morphogenesis / type I pneumocyte differentiation / Rac protein signal transduction / Signaling by RAS GAP mutants / Signaling by RAS GTPase mutants / positive regulation of Rac protein signal transduction / Activation of RAS in B cells / myoblast proliferation / negative regulation of transcription elongation by RNA polymerase II / Pausing and recovery of Tat-mediated HIV elongation / Tat-mediated HIV elongation arrest and recovery / RAS signaling downstream of NF1 loss-of-function variants / RUNX3 regulates p14-ARF / positive regulation of glial cell proliferation / skeletal muscle cell differentiation / 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 / cardiac muscle cell proliferation / Signalling to RAS / negative regulation of signal transduction / SHC-related events triggered by IGF1R / Activated NTRK2 signals through FRS2 and FRS3 / Tat-mediated elongation of the HIV-1 transcript / Estrogen-stimulated signaling through PRKCZ / Formation of HIV-1 elongation complex containing HIV-1 Tat / SHC-mediated cascade:FGFR3 / glial cell proliferation / MET activates RAS signaling / SHC-mediated cascade:FGFR2 / Formation of HIV elongation complex in the absence of HIV Tat / SHC-mediated cascade:FGFR4 / PTK6 Regulates RHO GTPases, RAS GTPase and MAP kinases / Signaling by PDGFRA transmembrane, juxtamembrane and kinase domain mutants / Signaling by PDGFRA extracellular domain mutants / Erythropoietin activates RAS / ubiquitin-like ligase-substrate adaptor activity / SHC-mediated cascade:FGFR1 / Signaling by FGFR4 in disease / Signaling by CSF3 (G-CSF) / RNA Polymerase II Transcription Elongation / FRS-mediated FGFR3 signaling / Formation of RNA Pol II elongation complex / Signaling by FLT3 ITD and TKD mutants / FRS-mediated FGFR2 signaling / FRS-mediated FGFR4 signaling / p38MAPK events / FRS-mediated FGFR1 signaling / Signaling by FGFR3 in disease / protein-membrane adaptor activity / striated muscle cell differentiation / Tie2 Signaling / Signaling by FGFR2 in disease / negative regulation of TORC1 signaling / GRB2 events in EGFR signaling / Signaling by FLT3 fusion proteins / SHC1 events in EGFR signaling / FLT3 Signaling / RNA Polymerase II Pre-transcription Events / Signaling by FGFR1 in disease / EGFR Transactivation by Gastrin / NCAM signaling for neurite out-growth / CD209 (DC-SIGN) signaling / GRB2 events in ERBB2 signaling / homeostasis of number of cells within a tissue / Downstream signal transduction / Insulin receptor signalling cascade / SHC1 events in ERBB2 signaling / negative regulation of autophagy / protein serine/threonine kinase binding / Ras activation upon Ca2+ influx through NMDA receptor / response to glucocorticoid / Constitutive Signaling by Overexpressed ERBB2 / Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants / transcription corepressor binding / VEGFR2 mediated cell proliferation
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 / PHOSPHATE ION / Chem-WYL / 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: 2.24 Å
AuthorsWijaya, A.J. / Zollman, D. / Farnaby, W. / Ciulli, A.
Funding support Germany, 1items
OrganizationGrant numberCountry
Boehringer Ingelheim Fonds (BIF) Germany
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

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Assembly

Deposited unit
H: Elongin-B
G: Elongin-C
F: von Hippel-Lindau disease tumor suppressor
D: Elongin-B
C: Elongin-C
B: von Hippel-Lindau disease tumor suppressor
E: Isoform 2B of GTPase KRas
A: Isoform 2B of GTPase KRas
hetero molecules


Theoretical massNumber of molelcules
Total (without water)139,87915
Polymers136,8118
Non-polymers3,0687
Water1,18966
1
H: Elongin-B
G: Elongin-C
F: von Hippel-Lindau disease tumor suppressor
E: Isoform 2B of GTPase KRas
hetero molecules


Theoretical massNumber of molelcules
Total (without water)69,8927
Polymers68,4054
Non-polymers1,4873
Water724
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
D: Elongin-B
C: Elongin-C
B: von Hippel-Lindau disease tumor suppressor
A: Isoform 2B of GTPase KRas
hetero molecules


Theoretical massNumber of molelcules
Total (without water)69,9878
Polymers68,4054
Non-polymers1,5824
Water724
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)72.253, 120.900, 81.016
Angle α, β, γ (deg.)90.000, 111.673, 90.000
Int Tables number4
Space group name H-MP1211
Space group name HallP2yb
Symmetry operation#1: x,y,z
#2: -x,y+1/2,-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
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ELOB, TCEB2 / Production host: Escherichia coli BL21(DE3) (bacteria) / 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
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ELOC, TCEB1 / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: Q15369
#3: Protein von Hippel-Lindau disease tumor suppressor


Mass: 24180.742 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: VHL / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: P40337
#4: Protein Isoform 2B of GTPase KRas


Mass: 21501.576 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: KRAS / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: P01116

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Non-polymers , 5 types, 73 molecules

#5: Chemical ChemComp-PO4 / PHOSPHATE ION


Mass: 94.971 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: PO4
#6: 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.: 2 / Source method: obtained synthetically / Formula: C50H62N14O6S2 / Feature type: SUBJECT OF INVESTIGATION
#7: Chemical ChemComp-GDP / GUANOSINE-5'-DIPHOSPHATE


Type: RNA linking / Mass: 443.201 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C10H15N5O11P2 / Feature type: SUBJECT OF INVESTIGATION / Comment: GDP, energy-carrying molecule*YM
#8: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Mg / Feature type: SUBJECT OF INVESTIGATION
#9: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 66 / 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: 2.07 Å3/Da / Density % sol: 40.58 %
Crystal growTemperature: 277.15 K / Method: vapor diffusion, sitting drop
Details: 20% w/v PEG 8000, 0.2 M lithium chloride, 0.1 M Tris pH 8.0

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Data collection

DiffractionMean temperature: 80 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X10SA / Wavelength: 0.99996 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Apr 20, 2023
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.99996 Å / Relative weight: 1
ReflectionResolution: 2.24→75.289 Å / Num. obs: 36523 / % possible obs: 90.6 % / Redundancy: 7.1 % / Biso Wilson estimate: 49.24 Å2 / CC1/2: 0.997 / Rmerge(I) obs: 0.142 / Rpim(I) all: 0.057 / Rrim(I) all: 0.153 / Net I/σ(I): 8
Reflection shellResolution: 2.242→2.3 Å / Redundancy: 7.2 % / Rmerge(I) obs: 1.315 / Mean I/σ(I) obs: 1.6 / Num. unique obs: 1826 / CC1/2: 0.707 / Rpim(I) all: 0.525 / % possible all: 60.6

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Processing

Software
NameVersionClassification
PHENIX1.19.2_4158refinement
PHENIX1.19.2_4158refinement
autoPROCdata reduction
autoPROCdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.24→55.86 Å / SU ML: 0.2722 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 41.9039
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2866 1879 5.15 %
Rwork0.2482 34585 -
obs0.2502 36464 58.85 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 60.48 Å2
Refinement stepCycle: LAST / Resolution: 2.24→55.86 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7614 0 207 66 7887
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00797992
X-RAY DIFFRACTIONf_angle_d1.198610883
X-RAY DIFFRACTIONf_chiral_restr0.08211234
X-RAY DIFFRACTIONf_plane_restr0.00681431
X-RAY DIFFRACTIONf_dihedral_angle_d17.44672986
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.24-2.30.483860.625593X-RAY DIFFRACTION2.1
2.3-2.370.18980.3373186X-RAY DIFFRACTION4.13
2.37-2.450.4289330.4285432X-RAY DIFFRACTION9.78
2.45-2.530.4092480.3766868X-RAY DIFFRACTION19.29
2.53-2.640.3931760.3611392X-RAY DIFFRACTION31.06
2.64-2.760.37741230.34822123X-RAY DIFFRACTION47.24
2.76-2.90.33721510.33763289X-RAY DIFFRACTION72.04
2.9-3.080.36852160.33033969X-RAY DIFFRACTION88.33
3.08-3.320.31742410.29234515X-RAY DIFFRACTION99.71
3.32-3.650.30422540.26634534X-RAY DIFFRACTION100
3.65-4.180.28612120.22994051X-RAY DIFFRACTION89.63
4.18-5.270.25312500.19554544X-RAY DIFFRACTION99.98
5.27-55.860.24662610.21854589X-RAY DIFFRACTION99.92

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