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- PDB-9l6f: Crystal structure of KRas G12D (GDP) in complex with ASP3082 -

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Entry
Database: PDB / ID: 9l6f
TitleCrystal structure of KRas G12D (GDP) in complex with ASP3082
Components
  • Elongin-B
  • Elongin-C
  • Isoform 2B of GTPase KRas
  • von Hippel-Lindau disease tumor suppressor
KeywordsHYDROLASE / GTPase
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 / negative regulation of transcription elongation by RNA polymerase II / RAS signaling downstream of NF1 loss-of-function variants / 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 / Signaling by CSF3 (G-CSF) / 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 / negative regulation of TORC1 signaling / Tie2 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 / negative regulation of autophagy / Ras activation upon Ca2+ influx through NMDA receptor / Insulin receptor signalling cascade / SHC1 events in ERBB2 signaling / 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: 3.18 Å
AuthorsAmano, Y. / Tateishi, Y.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Commun Chem / Year: 2025
Title: Discovery of KRAS(G12D) selective degrader ASP3082.
Authors: Yoshinari, T. / Nagashima, T. / Ishioka, H. / Inamura, K. / Nishizono, Y. / Tasaki, M. / Iguchi, K. / Suzuki, A. / Sato, C. / Nakayama, A. / Amano, Y. / Tateishi, Y. / Yamanaka, Y. / Osaki, ...Authors: Yoshinari, T. / Nagashima, T. / Ishioka, H. / Inamura, K. / Nishizono, Y. / Tasaki, M. / Iguchi, K. / Suzuki, A. / Sato, C. / Nakayama, A. / Amano, Y. / Tateishi, Y. / Yamanaka, Y. / Osaki, F. / Yoshino, M. / Kuramoto, K. / Imaizumi, T. / Hayakawa, M.
History
DepositionDec 24, 2024Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Sep 3, 2025Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: von Hippel-Lindau disease tumor suppressor
B: Elongin-C
C: Elongin-B
D: Isoform 2B of GTPase KRas
E: von Hippel-Lindau disease tumor suppressor
F: Elongin-C
G: Elongin-B
H: Isoform 2B of GTPase KRas
I: von Hippel-Lindau disease tumor suppressor
J: Elongin-C
K: Elongin-B
L: Isoform 2B of GTPase KRas
M: von Hippel-Lindau disease tumor suppressor
N: Elongin-C
O: Elongin-B
P: Isoform 2B of GTPase KRas
hetero molecules


Theoretical massNumber of molelcules
Total (without water)255,21328
Polymers248,87416
Non-polymers6,33912
Water00
1
A: von Hippel-Lindau disease tumor suppressor
B: Elongin-C
C: Elongin-B
hetero molecules


Theoretical massNumber of molelcules
Total (without water)43,9494
Polymers42,8323
Non-polymers1,1171
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4730 Å2
ΔGint-40 kcal/mol
Surface area17590 Å2
MethodPISA
2
D: Isoform 2B of GTPase KRas
hetero molecules


Theoretical massNumber of molelcules
Total (without water)19,8543
Polymers19,3871
Non-polymers4682
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area870 Å2
ΔGint-19 kcal/mol
Surface area8470 Å2
MethodPISA
3
E: von Hippel-Lindau disease tumor suppressor
F: Elongin-C
G: Elongin-B


Theoretical massNumber of molelcules
Total (without water)42,8323
Polymers42,8323
Non-polymers00
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4730 Å2
ΔGint-40 kcal/mol
Surface area16730 Å2
MethodPISA
4
H: Isoform 2B of GTPase KRas
hetero molecules


Theoretical massNumber of molelcules
Total (without water)20,9724
Polymers19,3871
Non-polymers1,5853
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area890 Å2
ΔGint-19 kcal/mol
Surface area8720 Å2
MethodPISA
5
I: von Hippel-Lindau disease tumor suppressor
J: Elongin-C
K: Elongin-B


Theoretical massNumber of molelcules
Total (without water)42,8323
Polymers42,8323
Non-polymers00
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4810 Å2
ΔGint-39 kcal/mol
Surface area17410 Å2
MethodPISA
6
L: Isoform 2B of GTPase KRas
hetero molecules


Theoretical massNumber of molelcules
Total (without water)20,9724
Polymers19,3871
Non-polymers1,5853
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area900 Å2
ΔGint-20 kcal/mol
Surface area8540 Å2
MethodPISA
7
M: von Hippel-Lindau disease tumor suppressor
N: Elongin-C
O: Elongin-B


Theoretical massNumber of molelcules
Total (without water)42,8323
Polymers42,8323
Non-polymers00
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4780 Å2
ΔGint-39 kcal/mol
Surface area16700 Å2
MethodPISA
8
P: Isoform 2B of GTPase KRas
hetero molecules


Theoretical massNumber of molelcules
Total (without water)20,9724
Polymers19,3871
Non-polymers1,5853
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area880 Å2
ΔGint-19 kcal/mol
Surface area8500 Å2
MethodPISA
Unit cell
Length a, b, c (Å)144.348, 58.905, 165.979
Angle α, β, γ (deg.)90.00, 104.30, 90.00
Int Tables number3
Space group name H-MP121

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Components

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Protein , 4 types, 16 molecules AEIMBFJNCGKODHLP

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


Mass: 18840.438 Da / Num. of mol.: 4
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
#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: 10843.420 Da / Num. of mol.: 4
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
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: 13147.781 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Details: Elongin-B / Source: (gene. exp.) Homo sapiens (human) / Gene: ELOB, TCEB2 / Production host: Escherichia coli (E. coli) / References: UniProt: Q15370
#4: Protein
Isoform 2B of GTPase KRas / K-Ras 2 / Ki-Ras / c-K-ras / c-Ki-ras


Mass: 19386.848 Da / Num. of mol.: 4 / Mutation: G12D
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 , 3 types, 12 molecules

#5: Chemical
ChemComp-A1L66 / ASP3082 / (2~{S},4~{R})-1-[(2~{S})-2-[4-[4-[[6-cyclopropyl-4-[(1~{S},4~{S})-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoranyl-5-methyl-1~{H}-indazol-4-yl)-2-(oxan-4-yloxy)quinazolin-8-yl]oxymethyl]phenyl]-1,2,3-triazol-1-yl]-3-methyl-butanoyl]-~{N}-[(1~{R})-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]-2-oxidanyl-ethyl]-4-oxidanyl-pyrrolidine-2-carboxamide / KRAS G12D inhibitor 17 / Setidegrasib


Mass: 1117.298 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C60H65FN12O7S / Feature type: SUBJECT OF INVESTIGATION
#6: Chemical
ChemComp-GDP / GUANOSINE-5'-DIPHOSPHATE


Type: RNA linking / Mass: 443.201 Da / Num. of mol.: 4 / 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.: 4 / Source method: obtained synthetically / Formula: Mg

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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: 2.75 Å3/Da / Density % sol: 55.23 %
Crystal growTemperature: 296 K / Method: vapor diffusion, sitting drop / Details: bis-tris propane, sodium formate, PEG3350 / PH range: 6.5 - 7.0

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Data collection

DiffractionMean temperature: 90 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SPring-8 / Beamline: BL41XU / Wavelength: 0.99999 Å
DetectorType: DECTRIS EIGER2 XE 16M / Detector: PIXEL / Date: Jan 20, 2023
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.99999 Å / Relative weight: 1
ReflectionResolution: 3.18→58.9 Å / Num. obs: 46338 / % possible obs: 100 % / Redundancy: 1.9 % / CC1/2: 0.998 / Rmerge(I) obs: 0.045 / Rpim(I) all: 0.045 / Rrim(I) all: 0.064 / Χ2: 0.98 / Net I/σ(I): 10 / Num. measured all: 89094
Reflection shellResolution: 3.18→3.29 Å / % possible obs: 100 % / Redundancy: 1.9 % / Rmerge(I) obs: 0.272 / Num. measured all: 8793 / Num. unique obs: 4518 / CC1/2: 0.932 / Rpim(I) all: 0.272 / Rrim(I) all: 0.385 / Χ2: 1.11 / Net I/σ(I) obs: 2.4

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Processing

Software
NameVersionClassification
REFMAC5.8.0257refinement
Aimlessdata scaling
XDSdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 7YCC,6GMR

7ycc

6gmr


Resolution: 3.18→48.76 Å / Cor.coef. Fo:Fc: 0.94 / Cor.coef. Fo:Fc free: 0.907 / SU B: 37.455 / SU ML: 0.598 / Cross valid method: THROUGHOUT / ESU R Free: 0.606 / Stereochemistry target values: MAXIMUM LIKELIHOOD
RfactorNum. reflection% reflectionSelection details
Rfree0.30537 2333 5 %RANDOM
Rwork0.2413 ---
obs0.24451 43994 99.92 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 140.972 Å2
Baniso -1Baniso -2Baniso -3
1--3.42 Å2-0 Å211.61 Å2
2---9.25 Å20 Å2
3---5.97 Å2
Refinement stepCycle: 1 / Resolution: 3.18→48.76 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms16069 0 440 0 16509
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0030.01216917
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.1031.69123001
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.07251995
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.20421.563915
X-RAY DIFFRACTIONr_dihedral_angle_3_deg21.752152835
X-RAY DIFFRACTIONr_dihedral_angle_4_deg17.5215137
X-RAY DIFFRACTIONr_chiral_restr0.0830.22212
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.0213390
X-RAY DIFFRACTIONr_gen_planes_other
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it7.07914.0268055
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it11.5121.0110025
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it7.54814.2958858
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other
X-RAY DIFFRACTIONr_long_range_B_refined18.65625820
X-RAY DIFFRACTIONr_long_range_B_other
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 3.18→3.262 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.408 177 -
Rwork0.41 3231 -
obs--99.94 %

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