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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 / RHOBTB3 ATPase cycle / negative regulation of receptor signaling pathway via JAK-STAT / transcription elongation factor activity / target-directed miRNA degradation / elongin complex / VCB complex / Replication of the SARS-CoV-1 genome / Cul5-RING ubiquitin ligase complex / forebrain astrocyte development ...regulation of cellular response to hypoxia / RHOBTB3 ATPase cycle / negative regulation of receptor signaling pathway via JAK-STAT / transcription elongation factor activity / target-directed miRNA degradation / elongin complex / VCB complex / Replication of the SARS-CoV-1 genome / Cul5-RING ubiquitin ligase complex / forebrain astrocyte development / Cul2-RING ubiquitin ligase complex / negative regulation of epithelial cell differentiation / regulation of synaptic transmission, GABAergic / epithelial tube branching involved in lung morphogenesis / type I pneumocyte differentiation / intracellular non-membrane-bounded organelle / Rac protein signal transduction / SUMOylation of ubiquitinylation proteins / negative regulation of transcription elongation by RNA polymerase II / skeletal muscle cell differentiation / positive regulation of Rac protein signal transduction / 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 / RAS signaling downstream of NF1 loss-of-function variants / RUNX3 regulates p14-ARF / HIV elongation arrest and recovery / Pausing and recovery of HIV elongation / ubiquitin-like ligase-substrate adaptor activity / SOS-mediated signalling / 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 / glial cell proliferation / SHC-related events triggered by IGF1R / Activated NTRK2 signals through FRS2 and FRS3 / Estrogen-stimulated signaling through PRKCZ / Formation of HIV elongation complex in the absence of HIV Tat / SHC-mediated cascade:FGFR3 / MET activates RAS signaling / PTK6 Regulates RHO GTPases, RAS GTPase and MAP kinases / negative regulation of signal transduction / Signaling by PDGFRA transmembrane, juxtamembrane and kinase domain mutants / Signaling by PDGFRA extracellular domain mutants / SHC-mediated cascade:FGFR2 / SHC-mediated cascade:FGFR4 / RNA Polymerase II Transcription Elongation / Signaling by FGFR4 in disease / SHC-mediated cascade:FGFR1 / Erythropoietin activates RAS / Formation of RNA Pol II elongation complex / protein-membrane adaptor activity / FRS-mediated FGFR3 signaling / Signaling by CSF3 (G-CSF) / positive regulation of glial cell proliferation / Signaling by FLT3 ITD and TKD mutants / homeostasis of number of cells within a tissue / FRS-mediated FGFR2 signaling / FRS-mediated FGFR4 signaling / Signaling by FGFR3 in disease / FRS-mediated FGFR1 signaling / p38MAPK events / Tie2 Signaling / negative regulation of TORC1 signaling / Signaling by FGFR2 in disease / striated muscle cell differentiation / RNA Polymerase II Pre-transcription Events / GRB2 events in EGFR signaling / SHC1 events in EGFR signaling / EGFR Transactivation by Gastrin / Signaling by FLT3 fusion proteins / FLT3 Signaling / Signaling by FGFR1 in disease / Ras activation upon Ca2+ influx through NMDA receptor / GRB2 events in ERBB2 signaling / NCAM signaling for neurite out-growth / CD209 (DC-SIGN) signaling / SHC1 events in ERBB2 signaling / Downstream signal transduction / Constitutive Signaling by Overexpressed ERBB2 / Insulin receptor signalling cascade / negative regulation of autophagy / small monomeric GTPase / transcription corepressor binding / G protein activity / Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants / VEGFR2 mediated cell proliferation / Evasion by RSV of host interferon responses / transcription elongation by RNA polymerase II / transcription initiation at RNA polymerase II promoter / positive regulation of cell differentiation / TP53 Regulates Transcription of DNA Repair Genes / FCERI mediated MAPK activation / Signaling by ERBB2 TMD/JMD mutants / regulation of long-term neuronal synaptic plasticity
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 B / Elongin-C ...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 B / Elongin-C / 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 family 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 / Ubiquitin family / Ubiquitin homologues / Small GTP-binding protein domain / 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
CitationJournal: 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

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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
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 / Guanosine 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 / 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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