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- PDB-9rkc: Crystal Structure of ACBI4-mediated ternary complex of KRAS G12D ... -

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Entry
Database: PDB / ID: 9rkc
TitleCrystal Structure of ACBI4-mediated ternary complex of KRAS G12D C118S GDP with pVHL:ElonginC:ElonginB
Components
  • Elongin-B
  • Elongin-C
  • GTPase KRas
  • von Hippel-Lindau disease tumor suppressor
KeywordsONCOPROTEIN / KRAS / TPD / PROTAC / VHL / ternary complex
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 / Replication of the SARS-CoV-1 genome / VCB complex / Cul5-RING ubiquitin ligase complex / response to mineralocorticoid ...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 / Replication of the SARS-CoV-1 genome / VCB complex / Cul5-RING ubiquitin ligase complex / response to mineralocorticoid / GMP binding / Cul2-RING ubiquitin ligase complex / forebrain astrocyte development / intracellular membraneless organelle / LRR domain binding / 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 / positive regulation of Rac protein signal transduction / Signaling by RAS GAP mutants / Signaling by RAS GTPase mutants / Activation of RAS in B cells / myoblast proliferation / skeletal muscle cell differentiation / Pausing and recovery of Tat-mediated HIV elongation / Tat-mediated HIV elongation arrest and recovery / RAS signaling downstream of NF1 loss-of-function variants / negative regulation of transcription elongation by RNA polymerase II / RUNX3 regulates p14-ARF / HIV elongation arrest and recovery / Pausing and recovery of HIV elongation / positive regulation of glial cell proliferation / 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 / Activated NTRK2 signals through FRS2 and FRS3 / SHC-related events triggered by IGF1R / Tat-mediated elongation of the HIV-1 transcript / Estrogen-stimulated signaling through PRKCZ / Formation of HIV-1 elongation complex containing HIV-1 Tat / glial cell proliferation / SHC-mediated cascade:FGFR3 / ubiquitin-like ligase-substrate adaptor activity / MET activates RAS signaling / Formation of HIV elongation complex in the absence of HIV Tat / SHC-mediated cascade:FGFR2 / PTK6 Regulates RHO GTPases, RAS GTPase and MAP kinases / Signaling by PDGFRA transmembrane, juxtamembrane and kinase domain mutants / Signaling by PDGFRA extracellular domain mutants / SHC-mediated cascade:FGFR4 / Erythropoietin activates RAS / SHC-mediated cascade:FGFR1 / Signaling by FGFR4 in disease / RNA Polymerase II Transcription Elongation / FRS-mediated FGFR3 signaling / Signaling by CSF3 (G-CSF) / 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 / Tie2 Signaling / negative regulation of TORC1 signaling / striated muscle cell differentiation / Signaling by FGFR2 in disease / RNA Polymerase II Pre-transcription Events / GRB2 events in EGFR signaling / SHC1 events in EGFR signaling / Signaling by FLT3 fusion proteins / FLT3 Signaling / Signaling by FGFR1 in disease / EGFR Transactivation by Gastrin / NCAM signaling for neurite out-growth / homeostasis of number of cells within a tissue / CD209 (DC-SIGN) signaling / GRB2 events in ERBB2 signaling / Downstream signal transduction / Insulin receptor signalling cascade / SHC1 events in ERBB2 signaling / Ras activation upon Ca2+ influx through NMDA receptor / negative regulation of autophagy / protein serine/threonine kinase binding / response to glucocorticoid / Constitutive Signaling by Overexpressed ERBB2 / Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants / VEGFR2 mediated cell proliferation / transcription corepressor binding / small monomeric GTPase
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 / Ubiquitin family / Small GTP-binding protein domain / 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 / 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: 2.19 Å
AuthorsKarolak, N.K. / Ciulli, A.
Funding support Germany, 1items
OrganizationGrant numberCountry
Boehringer Ingelheim Fonds (BIF) Germany
CitationJournal: J.Am.Chem.Soc. / Year: 2025
Title: Identification of a Highly Cooperative PROTAC Degrader Targeting GTP-Loaded KRAS(On) Alleles.
Authors: Vetma, V. / Puoti, I. / Karolak, N.K. / Chakraborti, S. / Diers, E. / Girardi, E. / Khan, S. / Kidd, G. / Kropatsch, K.G. / Mclennan, R. / O'Connor, S. / Samwer, M. / Trainor, N. / ...Authors: Vetma, V. / Puoti, I. / Karolak, N.K. / Chakraborti, S. / Diers, E. / Girardi, E. / Khan, S. / Kidd, G. / Kropatsch, K.G. / Mclennan, R. / O'Connor, S. / Samwer, M. / Trainor, N. / Whitworth, C. / Wijaya, A.J. / Wong, J.Y.F. / Zollman, D. / Farnaby, W. / Popow, J. / Ciulli, A. / Ettmayer, P. / McAulay, K.
History
DepositionJun 13, 2025Deposition site: PDBE / Processing site: PDBE
Revision 1.0Nov 12, 2025Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)124,46814
Polymers121,5928
Non-polymers2,8756
Water86548
1
A: Elongin-B
B: Elongin-C
C: von Hippel-Lindau disease tumor suppressor
D: GTPase KRas
hetero molecules


Theoretical massNumber of molelcules
Total (without water)62,2347
Polymers60,7964
Non-polymers1,4383
Water724
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
E: Elongin-B
F: Elongin-C
G: von Hippel-Lindau disease tumor suppressor
H: GTPase KRas
hetero molecules


Theoretical massNumber of molelcules
Total (without water)62,2347
Polymers60,7964
Non-polymers1,4383
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)71.915, 106.467, 82.742
Angle α, β, γ (deg.)90.000, 108.665, 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 AEBFCGDH

#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 (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
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
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: 19370.781 Da / Num. of mol.: 2
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

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Non-polymers , 4 types, 54 molecules

#5: Chemical ChemComp-A1JHI / (2~{S},4~{R})-1-[(2~{S})-2-[(5~{S})-5-[3-[(3~{S})-4-[4-[5-[(4~{S})-2-azanyl-3-cyano-4-methyl-6,7-dihydro-5~{H}-1-benzothiophen-4-yl]-1,2,4-oxadiazol-3-yl]pyrimidin-2-yl]-3-methyl-1,4-diazepan-1-yl]propyl]-4,5,6,7-tetrahydrobenzotriazol-1-yl]-3-methyl-butanoyl]-~{N}-[(1-methylindazol-6-yl)methyl]-4-oxidanyl-pyrrolidine-2-carboxamide


Mass: 970.198 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C50H63N15O4S / Feature type: SUBJECT OF INVESTIGATION
#6: 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
#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
Has protein modificationN

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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: 2.47 Å3/Da / Density % sol: 50.16 %
Crystal growTemperature: 293.15 K / Method: vapor diffusion, sitting drop
Details: 0.2 M Na2SO4, 15% w/v PEG 3,350, 0.1 M BIS-TRIS propane pH 7.79

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I24 / Wavelength: 0.6199 Å
DetectorType: DECTRIS EIGER2 X CdTe 9M / Detector: PIXEL / Date: Apr 24, 2025
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.6199 Å / Relative weight: 1
ReflectionResolution: 2.19→44.81 Å / Num. obs: 59951 / % possible obs: 97.6 % / Redundancy: 7.1 % / Biso Wilson estimate: 45.12 Å2 / CC1/2: 0.989 / Net I/σ(I): 4.1
Reflection shellResolution: 2.19→2.273 Å / Num. unique obs: 4959 / CC1/2: 0.318

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Processing

Software
NameVersionClassification
PHENIX1.19.2_4158refinement
xia2data reduction
xia2data scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.19→44.81 Å / SU ML: 0.4759 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 33.5181
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2745 1957 3.32 %
Rwork0.2323 57043 -
obs0.2336 59000 97.62 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 55.97 Å2
Refinement stepCycle: LAST / Resolution: 2.19→44.81 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7776 0 198 48 8022
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00418179
X-RAY DIFFRACTIONf_angle_d0.774911141
X-RAY DIFFRACTIONf_chiral_restr0.04971254
X-RAY DIFFRACTIONf_plane_restr0.00581468
X-RAY DIFFRACTIONf_dihedral_angle_d14.39053104
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.19-2.250.4381050.39213240X-RAY DIFFRACTION76.84
2.25-2.310.40781470.38864018X-RAY DIFFRACTION97.88
2.31-2.380.41351510.3694131X-RAY DIFFRACTION99.12
2.38-2.450.40831280.34474146X-RAY DIFFRACTION99.19
2.45-2.540.31611450.32354081X-RAY DIFFRACTION99.23
2.54-2.640.34451290.30354148X-RAY DIFFRACTION99.14
2.64-2.760.32931600.29334126X-RAY DIFFRACTION99.3
2.76-2.910.32631430.28034105X-RAY DIFFRACTION99.35
2.91-3.090.31891440.26744134X-RAY DIFFRACTION99.37
3.09-3.330.28111390.23594171X-RAY DIFFRACTION99.47
3.33-3.670.26741540.22724142X-RAY DIFFRACTION99.49
3.67-4.20.22441230.18734177X-RAY DIFFRACTION99.58
4.2-5.290.22741640.1654170X-RAY DIFFRACTION99.63
5.29-44.810.20681250.1864254X-RAY DIFFRACTION99.34
Refinement TLS params.Method: refined / Origin x: -16.1233036455 Å / Origin y: -27.8306074287 Å / Origin z: -11.332431241 Å
111213212223313233
T0.27479913046 Å20.00784702402071 Å2-0.00190388120968 Å2-0.314005376295 Å2-0.019141326655 Å2--0.323131804137 Å2
L0.399801969995 °2-0.0166237350352 °20.246987057988 °2-0.312934514474 °2-0.0871170716168 °2--0.757886193992 °2
S-0.012799513599 Å °-0.0536921779811 Å °-0.0694254855282 Å °-0.0501008364935 Å °0.0461366059801 Å °-0.00423024355402 Å °0.113561271988 Å °-0.0591366311408 Å °-0.0407122839137 Å °
Refinement TLS groupSelection details: all

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