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- PDB-9rkn: Crystal Structure of ACBI4-mediated ternary complex of KRAS G12R ... -

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Basic information

Entry
Database: PDB / ID: 9rkn
TitleCrystal Structure of ACBI4-mediated ternary complex of KRAS G12R GCP with pVHL:ElonginC:ElonginB
Components
  • Elongin-B
  • Elongin-C
  • Isoform 2B of 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
: / PHOSPHOMETHYLPHOSPHONIC ACID GUANYLATE ESTER / 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: 2.85 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: Isoform 2B of GTPase KRas
E: Elongin-B
F: Elongin-C
G: von Hippel-Lindau disease tumor suppressor
H: Isoform 2B of GTPase KRas
hetero molecules


Theoretical massNumber of molelcules
Total (without water)125,02817
Polymers121,7098
Non-polymers3,3209
Water362
1
A: Elongin-B
B: Elongin-C
C: von Hippel-Lindau disease tumor suppressor
D: Isoform 2B of GTPase KRas
hetero molecules


Theoretical massNumber of molelcules
Total (without water)62,65810
Polymers60,8544
Non-polymers1,8046
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
E: Elongin-B
F: Elongin-C
G: von Hippel-Lindau disease tumor suppressor
H: Isoform 2B of GTPase KRas
hetero molecules


Theoretical massNumber of molelcules
Total (without water)62,3707
Polymers60,8544
Non-polymers1,5163
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)72.303, 122.138, 80.328
Angle α, β, γ (deg.)90.000, 114.131, 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
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
d_1ens_1chain "A"
d_2ens_1(chain "E" and (resid 1 through 10 or (resid 11...
d_1ens_2(chain "B" and (resid 17 through 33 or (resid 34...
d_2ens_2(chain "F" and (resid 17 through 46 or resid 57...
d_1ens_3(chain "C" and (resid 62 through 109 or resid 111...
d_2ens_3(chain "G" and ((resid 62 and (name N or name...
d_1ens_4(chain "D" and (resid 1 through 11 or (resid 12...
d_2ens_4(chain "H" and (resid 1 through 28 or (resid 37...

NCS domain segments:
Dom-IDComponent-IDEns-IDBeg auth comp-IDBeg label comp-IDEnd auth comp-IDEnd label comp-IDAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
d_11ens_1METMETLYSLYSAA1 - 1051 - 104
d_21ens_1METMETARGARGEE1 - 801 - 80
d_22ens_1THRTHRLYSLYSEE84 - 10484 - 104
d_11ens_2METMETCYSCYSBB17 - 1122 - 97
d_21ens_2METMETLEULEUFF17 - 462 - 31
d_22ens_2THRTHRCYSCYSFF57 - 11242 - 97
d_11ens_3VALVALILEILECC62 - 10911 - 58
d_12ens_3SERSERALAALACC111 - 20760 - 156
d_21ens_3VALVALILEILEGG62 - 10911 - 58
d_22ens_3SERSERALAALAGG111 - 20760 - 156
d_11ens_4METMETPHEPHEDD1 - 282 - 29
d_12ens_4GLUGLUASPASPDD37 - 11938 - 120
d_13ens_4SERSERGLUGLUDD122 - 168123 - 169
d_14ens_4A1JHIA1JHIA1JHIA1JHICJ301
d_15ens_4GCPGCPGCPGCPDK301
d_21ens_4METMETGLUGLUHH1 - 1682 - 169
d_22ens_4A1JHIA1JHIA1JHIA1JHIHO201
d_23ens_4GCPGCPGCPGCPHP202

NCS ensembles :
ID
ens_1
ens_2
ens_3
ens_4

NCS oper:
IDCodeMatrixVector
1given(-0.992023941337, -0.104555397831, 0.0704036121091), (-0.10264202635, 0.994257459069, 0.0302773762519), (-0.0731649796042, 0.0228095127136, -0.997058981149)-44.2973252574, -4.03863789013, -50.1028509259
2given(-0.992665505665, -0.104497575991, 0.0607902169286), (-0.0986227495573, 0.990796050566, 0.0927186035981), (-0.0699195761712, 0.0860432611856, -0.993834900812)-44.6674618578, -1.2409817443, -47.2356554293
3given(-0.999585114741, -0.0147100433109, 0.0247631382267), (-0.00972856452153, 0.981652717522, 0.190429244642), (-0.0271100243709, 0.190109328567, -0.981388551885)-44.0337400568, 3.99467488891, -43.4418025683
4given(-0.999857151908, -0.00795498431502, 0.0149128804674), (-0.00476406803506, 0.979185206436, 0.202912875771), (-0.0162166406831, 0.202812844076, -0.979083229783)-44.3653223082, 4.64203085477, -43.2344347008

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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 Isoform 2B of GTPase KRas / K-Ras 2 / Ki-Ras / c-K-ras / c-Ki-ras


Mass: 19428.953 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, small monomeric GTPase

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Non-polymers , 5 types, 11 molecules

#5: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: SO4
#6: 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
#7: Chemical ChemComp-GCP / PHOSPHOMETHYLPHOSPHONIC ACID GUANYLATE ESTER


Mass: 521.208 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C11H18N5O13P3 / Comment: GMP-PCP, energy-carrying molecule analogue*YM
#8: Chemical ChemComp-MG / MAGNESIUM ION


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


Mass: 18.015 Da / Num. of mol.: 2 / 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: 2.66 Å3/Da / Density % sol: 53.75 %
Crystal growTemperature: 293.15 K / Method: vapor diffusion, sitting drop
Details: 0.14 M Ammonium sulfate, 25% w/v Polyethylene glycol 3,350, 0.1M BIS-TRIS pH 5.8

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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: 2.85→58.05 Å / Num. obs: 29820 / % possible obs: 99.61 % / Redundancy: 7.1 % / Biso Wilson estimate: 59.63 Å2 / CC1/2: 0.981 / Net I/σ(I): 3.2
Reflection shellResolution: 2.85→2.952 Å / Num. unique obs: 2920 / CC1/2: 0.302

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Processing

Software
NameVersionClassification
PHENIX1.19.2_4158refinement
xia2data reduction
xia2data scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.85→58.05 Å / SU ML: 0.6332 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 34.0884
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2751 1524 5.24 %
Rwork0.2259 27564 -
obs0.2285 29088 97.18 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 65.55 Å2
Refinement stepCycle: LAST / Resolution: 2.85→58.05 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7667 0 221 2 7890
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00228078
X-RAY DIFFRACTIONf_angle_d0.62811018
X-RAY DIFFRACTIONf_chiral_restr0.04661258
X-RAY DIFFRACTIONf_plane_restr0.00381451
X-RAY DIFFRACTIONf_dihedral_angle_d13.063040
Refine LS restraints NCS
Ens-IDDom-IDAsym-IDAuth asym-IDRefine-IDTypeRms dev position (Å)
ens_1d_2AAX-RAY DIFFRACTIONTorsion NCS1.12347104584
ens_2d_2BBX-RAY DIFFRACTIONTorsion NCS0.874214939109
ens_3d_2CCX-RAY DIFFRACTIONTorsion NCS0.861980425864
ens_4d_2DDX-RAY DIFFRACTIONTorsion NCS0.910590755548
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.85-2.940.39271150.3811767X-RAY DIFFRACTION69.91
2.94-3.040.37621280.36522569X-RAY DIFFRACTION99.45
3.04-3.160.4081550.3512555X-RAY DIFFRACTION99.85
3.16-3.310.38431570.30722570X-RAY DIFFRACTION99.96
3.31-3.480.33651280.26462579X-RAY DIFFRACTION99.96
3.48-3.70.3011380.23832563X-RAY DIFFRACTION100
3.7-3.990.25691190.21252586X-RAY DIFFRACTION99.82
3.99-4.390.22241240.17872598X-RAY DIFFRACTION100
4.39-5.020.24581400.16322590X-RAY DIFFRACTION99.96
5.02-6.320.25471560.20632579X-RAY DIFFRACTION100
6.33-58.050.20851640.18492608X-RAY DIFFRACTION99.78
Refinement TLS params.Method: refined / Origin x: -21.9330306763 Å / Origin y: -20.1092880332 Å / Origin z: -23.0167146995 Å
111213212223313233
T0.334735251806 Å20.010116314312 Å20.0352228522106 Å2-0.305890307484 Å2-0.0226678142421 Å2--0.450650310521 Å2
L0.629035461985 °20.0621642296111 °2-0.0373098064067 °2-0.359321686039 °2-0.0808214878175 °2--0.597671554991 °2
S-0.0331937505188 Å °-0.0118011311742 Å °0.086958016278 Å °-0.0293258280005 Å °0.0119929472774 Å °0.010894439117 Å °-0.0186067516254 Å °-0.05592236998 Å °0.0238930534924 Å °
Refinement TLS groupSelection details: all

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