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- PDB-9c3z: Crystal structure of GDP-bound KRAS G12D/G60R: Suppressing G12D o... -

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Basic information

Entry
Database: PDB / ID: 9c3z
TitleCrystal structure of GDP-bound KRAS G12D/G60R: Suppressing G12D oncogenicity via second-site G60R mutation
ComponentsIsoform 2B of GTPase KRas
KeywordsONCOPROTEIN / KRAS / RAS / nucleotide-binding protein / signaling protein / G12D / G60R
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: 1.8 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)39,9096
Polymers38,9742
Non-polymers9354
Water81145
1
A: Isoform 2B of GTPase KRas
hetero molecules


Theoretical massNumber of molelcules
Total (without water)19,9543
Polymers19,4871
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)19,9543
Polymers19,4871
Non-polymers4682
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)84.540, 84.540, 41.560
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: 19486.990 Da / Num. of mol.: 2 / Mutation: G12D, G60R
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: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 45 / 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: 2.2 Å3/Da / Density % sol: 44.09 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / Details: 0.2 M Lithium acetate, 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 twin
Crystal-IDIDOperatorDomain-IDFraction
11H, K, L10.278
11-h,-k,l20.266
11K, H, -L30.207
11-K, -H, -L40.249
ReflectionResolution: 1.8→50 Å / Num. obs: 30789 / % possible obs: 99.9 % / Redundancy: 6.6 % / CC1/2: 0.995 / Rmerge(I) obs: 0.101 / Rrim(I) all: 0.11 / Net I/σ(I): 11.87
Reflection shell
Resolution (Å)Rmerge(I) obsNum. unique obsCC1/2Rrim(I) allDiffraction-ID
1.8-1.850.81722790.6870.8851
1.85-1.90.6422150.7920.6911
1.9-1.950.50421630.8310.5451
1.95-2.010.39721020.8930.431
2.01-2.080.32620400.8970.3541
2.08-2.150.26919690.9160.2921
2.15-2.230.21718950.9390.2351
2.23-2.320.17818140.960.1941
2.32-2.430.15617450.9590.171
2.43-2.550.1416770.9470.1561
2.55-2.680.12615800.9710.1361
2.68-2.850.11615160.9740.1261
2.85-3.040.10614330.980.1151
3.04-3.290.10212950.980.1111
3.29-3.60.09412090.9810.1021
3.6-4.020.09210900.9840.11
4.02-4.650.0859750.9830.0921
4.65-5.690.088140.9890.0871
5.69-8.050.0736310.9890.0781
8.05-500.0643470.9970.0691

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Processing

Software
NameVersionClassification
REFMAC5.8.0267refinement
XSCALEdata scaling
PDB_EXTRACT3.27data extraction
XDSdata reduction
PHENIXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5US4

5us4


Resolution: 1.8→42.27 Å / Cor.coef. Fo:Fc: 0.98 / Cor.coef. Fo:Fc free: 0.962 / SU B: 3.507 / SU ML: 0.055 / Cross valid method: THROUGHOUT / ESU R: 0.018 / ESU R Free: 0.02 / Stereochemistry target values: MAXIMUM LIKELIHOOD
RfactorNum. reflection% reflectionSelection details
Rfree0.17394 2004 6.5 %RANDOM
Rwork0.12299 ---
obs0.12629 28784 99.94 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 32.486 Å2
Baniso -1Baniso -2Baniso -3
1--2.31 Å2-0 Å2-0 Å2
2---2.31 Å2-0 Å2
3---4.62 Å2
Refinement stepCycle: 1 / Resolution: 1.8→42.27 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2508 0 58 47 2613
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0070.0122606
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.6261.6783533
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.7575314
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.79822.587143
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.51915450
X-RAY DIFFRACTIONr_dihedral_angle_4_deg20.3111518
X-RAY DIFFRACTIONr_chiral_restr0.1070.2351
X-RAY DIFFRACTIONr_gen_planes_refined0.0080.021938
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_it1.4612.751268
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it1.8974.1241578
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it1.822.9041338
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other
X-RAY DIFFRACTIONr_long_range_B_refined3.23937.9753908
X-RAY DIFFRACTIONr_long_range_B_other
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
Refine LS restraints NCS

Ens-ID: 1 / Number: 4638 / Refine-ID: X-RAY DIFFRACTION / Type: interatomic distance / Rms dev position: 0.11 Å / Weight position: 0.05

Dom-IDAuth asym-ID
1A
2B
LS refinement shellResolution: 1.8→1.847 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.251 158 -
Rwork0.19 2118 -
obs--99.96 %
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
10.74160.0072-0.09080.7567-0.07340.62050.04210.0178-0.004-0.0078-0.03140.03460.046-0.0303-0.01060.01340.0005-0.0020.0041-0.00490.054-11.30830.252-9.729
20.77080.1064-0.03470.7764-0.01560.75960.01020.0290.0034-0.0363-0.006-0.0188-0.05220.0618-0.00410.0059-0.0036-0.00260.00650.00180.058212.66617.16312.048
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A1 - 168
2X-RAY DIFFRACTION1A201 - 202
3X-RAY DIFFRACTION2B1 - 166
4X-RAY DIFFRACTION2B201 - 202

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