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- PDB-9c3m: Crystal structure of GDP-bound KRAS G12D/F28K: Suppressing G12D o... -

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Basic information

Entry
Database: PDB / ID: 9c3m
TitleCrystal structure of GDP-bound KRAS G12D/F28K: Suppressing G12D oncogenicity via second-site F28K mutation
ComponentsIsoform 2B of GTPase KRas
KeywordsONCOPROTEIN / KRAS / RAS / nucleotide-binding protein / signaling protein oncoprotein / G12D / F28K
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 / SHC-mediated cascade:FGFR1 / Signaling by FGFR4 in disease / FRS-mediated FGFR3 signaling / Signaling by CSF3 (G-CSF) / Signaling by FLT3 ITD and TKD mutants / FRS-mediated FGFR2 signaling / FRS-mediated FGFR4 signaling / FRS-mediated FGFR1 signaling / p38MAPK events / Signaling by FGFR3 in disease / protein-membrane adaptor activity / Tie2 Signaling / striated muscle cell differentiation / Signaling by FGFR2 in disease / GRB2 events in EGFR signaling / Signaling by FLT3 fusion proteins / SHC1 events in EGFR signaling / 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 / Downstream signal transduction / GRB2 events in ERBB2 signaling / Insulin receptor signalling cascade / Ras activation upon Ca2+ influx through NMDA receptor / 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 / female pregnancy / RAF activation / Signaling by ERBB2 TMD/JMD mutants / Signaling by SCF-KIT / Constitutive Signaling by EGFRvIII / Signaling by high-kinase activity BRAF mutants / regulation of long-term neuronal synaptic plasticity / MAP2K and MAPK activation / Signaling by ERBB2 ECD mutants / visual learning / Signaling by ERBB2 KD Mutants / 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: 1.74 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 1, 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)40,15311
Polymers38,7382
Non-polymers1,4159
Water2,144119
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A: Isoform 2B of GTPase KRas
hetero molecules


Theoretical massNumber of molelcules
Total (without water)20,2217
Polymers19,3691
Non-polymers8526
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Isoform 2B of GTPase KRas
hetero molecules


Theoretical massNumber of molelcules
Total (without water)19,9324
Polymers19,3691
Non-polymers5643
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)30.751, 39.132, 62.897
Angle α, β, γ (deg.)98.15, 86.32, 104.91
Int Tables number1
Space group name H-MP1

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Components

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


Mass: 19368.854 Da / Num. of mol.: 2 / Mutation: G12D, F28K
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-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
#3: Chemical ChemComp-MG / MAGNESIUM ION


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


Mass: 96.063 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: SO4 / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 119 / 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: 1.87 Å3/Da / Density % sol: 34.16 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / Details: 3.2 M (NH4)2SO4; 0.1 M Na3Cit pH 5

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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: Oct 2, 2010
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9791 Å / Relative weight: 1
ReflectionResolution: 1.74→37.49 Å / Num. obs: 26971 / % possible obs: 93.7 % / Redundancy: 3.6 % / CC1/2: 0.994 / Rmerge(I) obs: 0.116 / Rrim(I) all: 0.137 / Net I/σ(I): 8.99
Reflection shell
Resolution (Å)Rmerge(I) obsNum. unique obsCC1/2Rrim(I) allDiffraction-ID
1.74-1.790.85119970.6580.9921
1.79-1.830.69819480.740.8181
1.83-1.890.58319090.7910.6841
1.89-1.950.46918390.8770.5471
1.95-2.010.37717800.9120.4421
2.01-2.080.31317040.9310.3681
2.08-2.160.25116500.9390.2961
2.16-2.250.18714520.9650.2231
2.25-2.350.17315530.9730.2031
2.35-2.460.16215140.9760.191
2.46-2.590.13514020.9830.1581
2.59-2.750.12113780.9850.1421
2.75-2.940.10312350.9880.1221
2.94-3.180.08511630.9910.1011
3.18-3.480.06710800.9930.0791
3.48-3.890.0559580.9920.0661
3.89-4.490.0467970.9940.0561
4.49-5.50.0457290.9950.0521
5.5-7.780.0465760.9950.0541
7.78-37.490.0363070.9980.0421

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Processing

Software
NameVersionClassification
PHENIX(1.21_5207: ???)refinement
XSCALEdata scaling
PDB_EXTRACT3.27data extraction
XDSdata reduction
PHENIXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5US4

5us4


Resolution: 1.74→34.13 Å / SU ML: 0.23 / Cross valid method: THROUGHOUT / σ(F): 1.98 / Phase error: 23.5 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.2222 1347 5 %RANDOM
Rwork0.1831 ---
obs0.1851 26966 93.72 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 1.74→34.13 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2676 0 83 119 2878
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0072822
X-RAY DIFFRACTIONf_angle_d0.9613830
X-RAY DIFFRACTIONf_dihedral_angle_d18.7171063
X-RAY DIFFRACTIONf_chiral_restr0.057425
X-RAY DIFFRACTIONf_plane_restr0.009488
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.74-1.80.33281340.27312560X-RAY DIFFRACTION93
1.8-1.870.2771370.24352605X-RAY DIFFRACTION96
1.87-1.960.24921350.20962557X-RAY DIFFRACTION94
1.96-2.060.2361340.19482549X-RAY DIFFRACTION92
2.06-2.190.2621300.1942469X-RAY DIFFRACTION91
2.19-2.360.24121310.18142507X-RAY DIFFRACTION92
2.36-2.60.24181370.17732616X-RAY DIFFRACTION96
2.6-2.970.2251380.18352625X-RAY DIFFRACTION96
2.97-3.750.19711360.16182567X-RAY DIFFRACTION94
3.75-34.130.17311350.16332564X-RAY DIFFRACTION94
Refinement TLS params.Method: refined / Origin x: -2.7432 Å / Origin y: -20.5898 Å / Origin z: -14.1211 Å
111213212223313233
T0.0812 Å20.0085 Å20.0053 Å2-0.1116 Å20.0257 Å2--0.0873 Å2
L0.5282 °20.2314 °20.1943 °2-0.6345 °20.3942 °2--0.4655 °2
S-0.0079 Å °0.0465 Å °-0.0041 Å °-0.0441 Å °0.0263 Å °-0.0174 Å °-0.008 Å °0.027 Å °-0.0173 Å °
Refinement TLS groupSelection details: all

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