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- PDB-9c41: Crystal structure of GDP-bound KRAS G12D/E62Q: Suppressing G12D o... -

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Basic information

Entry
Database: PDB / ID: 9c41
TitleCrystal structure of GDP-bound KRAS G12D/E62Q: Suppressing G12D oncogenicity via second-site E62Q mutation
ComponentsIsoform 2B of GTPase KRas
KeywordsONCOPROTEIN / KRAS / RAS / nucleotide-binding protein / signaling protein / G12D / E62Q
Function / homology
Function and homology information


response to mineralocorticoid / GMP binding / forebrain astrocyte development / LRR domain binding / regulation of synaptic transmission, GABAergic / negative regulation of epithelial cell differentiation / response to isolation stress / response to gravity / epithelial tube branching involved in lung morphogenesis / type I pneumocyte differentiation ...response to mineralocorticoid / GMP binding / forebrain astrocyte development / LRR domain binding / regulation of synaptic transmission, GABAergic / negative regulation of epithelial cell differentiation / response to isolation stress / 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 / RAS signaling downstream of NF1 loss-of-function variants / RUNX3 regulates p14-ARF / 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 / Activated NTRK2 signals through FRS2 and FRS3 / SHC-related events triggered by IGF1R / Estrogen-stimulated signaling through PRKCZ / glial cell proliferation / SHC-mediated cascade:FGFR3 / MET activates RAS signaling / 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 / Signaling by FGFR4 in disease / SHC-mediated cascade:FGFR1 / Signaling by CSF3 (G-CSF) / FRS-mediated FGFR3 signaling / Signaling by FLT3 ITD and TKD mutants / FRS-mediated FGFR2 signaling / FRS-mediated FGFR4 signaling / protein-membrane adaptor activity / p38MAPK events / FRS-mediated FGFR1 signaling / Signaling by FGFR3 in disease / Tie2 Signaling / striated muscle cell differentiation / Signaling by FGFR2 in disease / 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 / CD209 (DC-SIGN) signaling / homeostasis of number of cells within a tissue / GRB2 events in ERBB2 signaling / Downstream signal transduction / Ras activation upon Ca2+ influx through NMDA receptor / Insulin receptor signalling cascade / SHC1 events in ERBB2 signaling / response to glucocorticoid / Constitutive Signaling by Overexpressed ERBB2 / Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants / VEGFR2 mediated cell proliferation / small monomeric GTPase / FCERI mediated MAPK activation / liver development / RAF activation / Signaling by ERBB2 TMD/JMD mutants / female pregnancy / Signaling by SCF-KIT / Signaling by high-kinase activity BRAF mutants / Constitutive Signaling by EGFRvIII / regulation of long-term neuronal synaptic plasticity / MAP2K and MAPK activation / Signaling by ERBB2 ECD mutants / Signaling by ERBB2 KD Mutants / visual learning / cytoplasmic side of plasma membrane / cytokine-mediated signaling pathway / Regulation of RAS by GAPs / Signaling by CSF1 (M-CSF) in myeloid cells / RAS processing / Negative regulation of MAPK pathway / Signaling by RAF1 mutants / Signaling by moderate kinase activity BRAF mutants / Paradoxical activation of RAF signaling by kinase inactive BRAF / Signaling downstream of RAS mutants / GDP binding / Signaling by BRAF and RAF1 fusions / positive regulation of cellular senescence / DAP12 signaling / MAPK cascade / Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants
Similarity search - Function
Small GTPase, Ras-type / Small GTPase Ras domain profile. / Ran (Ras-related nuclear proteins) /TC4 subfamily of small GTPases / 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 / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
GUANOSINE-5'-DIPHOSPHATE / GTPase KRas
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.94 Å
AuthorsTran, T.H. / Dharmaiah, S. / Simanshu, D.K.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Cancer Institute (NIH/NCI)75N91019D00024 United States
CitationJournal: Biorxiv / Year: 2024
Title: Comprehensive structure-function analysis reveals gain- and loss-of-function mechanisms impacting oncogenic KRAS activity.
Authors: Kwon, J.J. / Dilly, J. / Liu, S. / Kim, E. / Bian, Y. / Dharmaiah, S. / Tran, T.H. / Kapner, K.S. / Ly, S.H. / Yang, X. / Rabara, D. / Waybright, T.J. / Giacomelli, A.O. / Hong, A.L. / ...Authors: Kwon, J.J. / Dilly, J. / Liu, S. / Kim, E. / Bian, Y. / Dharmaiah, S. / Tran, T.H. / Kapner, K.S. / Ly, S.H. / Yang, X. / Rabara, D. / Waybright, T.J. / Giacomelli, A.O. / Hong, A.L. / Misek, S. / Wang, B. / Ravi, A. / Doench, J.G. / Beroukhim, R. / Lemke, C.T. / Haigis, K.M. / Esposito, D. / Root, D.E. / Nissley, D.V. / Stephen, A.G. / McCormick, F. / Simanshu, D.K. / Hahn, W.C. / Aguirre, A.J.
History
DepositionJun 2, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 8, 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: Isoform 2B of GTPase KRas
B: Isoform 2B of GTPase KRas
hetero molecules


Theoretical massNumber of molelcules
Total (without water)39,8037
Polymers38,7722
Non-polymers1,0315
Water97354
1
A: Isoform 2B of GTPase KRas
hetero molecules


Theoretical massNumber of molelcules
Total (without water)19,8533
Polymers19,3861
Non-polymers4682
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Isoform 2B of GTPase KRas
hetero molecules


Theoretical massNumber of molelcules
Total (without water)19,9494
Polymers19,3861
Non-polymers5643
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)84.910, 84.910, 41.890
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number143
Space group name H-MP3

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Components

#1: Protein Isoform 2B of GTPase KRas / K-Ras 2 / Ki-Ras / c-K-ras / c-Ki-ras


Mass: 19385.861 Da / Num. of mol.: 2 / Mutation: G12D, E62Q
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
#2: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Mg / Feature type: SUBJECT OF INVESTIGATION
#3: 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
#4: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Formula: SO4 / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 54 / Source method: isolated from a natural source / Formula: H2O
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: 2.26 Å3/Da / Density % sol: 45.46 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / Details: 0.2 M Sodium Formate, 2.2 M Ammonium Sulfate

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 24-ID-E / Wavelength: 0.9791 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Jul 14, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9791 Å / Relative weight: 1
Reflection twinOperator: -h,-k,l / Fraction: 0.47
ReflectionResolution: 1.94→50 Å / Num. obs: 24202 / % possible obs: 96.7 % / Redundancy: 2.3 % / CC1/2: 0.986 / Rmerge(I) obs: 0.079 / Rrim(I) all: 0.101 / Net I/σ(I): 7.99
Reflection shell
Resolution (Å)Rmerge(I) obsNum. unique obsCC1/2Rrim(I) allDiffraction-ID
1.94-1.990.33618660.5410.4321
1.99-2.050.26117520.6930.3371
2.05-2.10.22217570.7270.2851
2.1-2.170.19916640.7340.2561
2.17-2.240.15916100.8360.2041
2.24-2.320.13215290.8750.171
2.32-2.410.11614420.8980.1491
2.41-2.50.10914600.9210.1391
2.5-2.620.1113550.8890.1411
2.62-2.740.10212990.9250.1311
2.74-2.890.09512450.9310.1211
2.89-3.070.09411850.9140.1221
3.07-3.280.08510650.9510.1091
3.28-3.540.07610170.9320.0991
3.54-3.880.0749640.9520.0941
3.88-4.340.0788540.9510.0991
4.34-5.010.0677660.9660.0861
5.01-6.140.0646130.9680.0811
6.14-8.680.0564890.9760.0711
8.68-500.0452700.9910.0571

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Processing

Software
NameVersionClassification
REFMAC5.8.0405refinement
XSCALEdata scaling
PDB_EXTRACT3.27data extraction
XDSdata reduction
PHENIXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5US4

5us4


Resolution: 1.94→42.46 Å / Cor.coef. Fo:Fc: 0.971 / Cor.coef. Fo:Fc free: 0.962 / SU B: 2.353 / SU ML: 0.072 / Cross valid method: THROUGHOUT / ESU R: 0.028 / ESU R Free: 0.024 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN USED IF PRESENT IN THE INPUT
RfactorNum. reflection% reflectionSelection details
Rfree0.16116 2026 8.3 %RANDOM
Rwork0.13889 ---
obs0.14077 22261 97.02 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 35.918 Å2
Baniso -1Baniso -2Baniso -3
1--2.37 Å2-0 Å2-0 Å2
2---2.37 Å2-0 Å2
3---4.74 Å2
Refinement stepCycle: 1 / Resolution: 1.94→42.46 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2544 0 63 54 2661
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0040.0122650
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.0621.6583592
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.8835321
X-RAY DIFFRACTIONr_dihedral_angle_2_deg4.353517
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.90310462
X-RAY DIFFRACTIONr_dihedral_angle_4_deg
X-RAY DIFFRACTIONr_chiral_restr0.0820.2412
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.021952
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_it2.1713.4181284
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it3.3816.1291599
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it2.6613.7641366
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other
X-RAY DIFFRACTIONr_long_range_B_refined6.03941.363962
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: 1.94→2.045 Å / Total num. of bins used: 10
RfactorNum. reflection% reflection
Rfree0.24 301 -
Rwork0.203 3312 -
obs--98.61 %

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