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- PDB-9c3k: Crystal structure of GDP-bound KRAS G12D/M67R: Suppressing G12D o... -

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Basic information

Entry
Database: PDB / ID: 9c3k
TitleCrystal structure of GDP-bound KRAS G12D/M67R: Suppressing G12D oncogenicity via second-site M67R mutation
ComponentsIsoform 2B of GTPase KRas
KeywordsONCOPROTEIN / KRAS / RAS / nucleotide-binding protein / signaling protein / G12D / M67R
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: 1.7 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)39,7616
Polymers38,8262
Non-polymers9354
Water2,144119
1
A: Isoform 2B of GTPase KRas
hetero molecules


Theoretical massNumber of molelcules
Total (without water)19,8803
Polymers19,4131
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)19,8803
Polymers19,4131
Non-polymers4682
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)84.630, 84.630, 41.760
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number143
Space group name H-MP3
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11(chain A and (resid 2 through 51 or (resid 52...
21(chain B and (resid 2 through 40 or (resid 41...

NCS domain segments:

Ens-ID: 1

Dom-IDComponent-IDBeg auth comp-IDBeg label comp-IDEnd auth comp-IDEnd label comp-IDSelection detailsAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
11THRTHRCYSCYS(chain A and (resid 2 through 51 or (resid 52...AA2 - 513 - 52
12LEULEULEULEU(chain A and (resid 2 through 51 or (resid 52...AA5253
13METMETLYSLYS(chain A and (resid 2 through 51 or (resid 52...AA1 - 1672 - 168
14METMETLYSLYS(chain A and (resid 2 through 51 or (resid 52...AA1 - 1672 - 168
15METMETLYSLYS(chain A and (resid 2 through 51 or (resid 52...AA1 - 1672 - 168
16METMETLYSLYS(chain A and (resid 2 through 51 or (resid 52...AA1 - 1672 - 168
21THRTHRTYRTYR(chain B and (resid 2 through 40 or (resid 41...BB2 - 403 - 41
22ARGARGARGARG(chain B and (resid 2 through 40 or (resid 41...BB4142
23THRTHRLYSLYS(chain B and (resid 2 through 40 or (resid 41...BB2 - 1673 - 168
24THRTHRLYSLYS(chain B and (resid 2 through 40 or (resid 41...BB2 - 1673 - 168
25THRTHRLYSLYS(chain B and (resid 2 through 40 or (resid 41...BB2 - 1673 - 168
26THRTHRLYSLYS(chain B and (resid 2 through 40 or (resid 41...BB2 - 1673 - 168

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Components

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


Mass: 19412.846 Da / Num. of mol.: 2 / Mutation: G12D, M67R
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: 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: 2.22 Å3/Da / Density % sol: 44.69 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / Details: 0.2 M NH4 Acetate; 2.2 M (NH4)2SO4

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 24-ID-E / Wavelength: 0.9792 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Nov 19, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9792 Å / Relative weight: 1
Reflection twinOperator: -h,-k,l / Fraction: 0.49
ReflectionResolution: 1.7→20 Å / Num. obs: 36795 / % possible obs: 99.9 % / Redundancy: 5.208 % / Biso Wilson estimate: 37.718 Å2 / CC1/2: 0.997 / Rmerge(I) obs: 0.074 / Rrim(I) all: 0.083 / Χ2: 0.904 / Net I/σ(I): 12
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. measured obsNum. possibleNum. unique obsCC1/2Rrim(I) all% possible all
1.7-1.744.9850.7472.1713683274827450.5610.83899.9
1.74-1.795.3160.6082.9614039264126410.7080.676100
1.79-1.845.3250.4783.8713797259125910.7910.532100
1.84-1.95.340.3694.9813403251025100.8620.411100
1.9-1.965.2650.2816.712905245224510.8990.313100
1.96-2.035.1890.2248.112002231523130.9280.2599.9
2.03-2.114.9960.1849.711421228922860.9440.20799.9
2.11-2.194.8670.15411.410658219021900.9580.173100
2.19-2.295.4280.13513.9611410210221020.9730.15100
2.29-2.45.4190.12315.3510664196919680.9730.13799.9
2.4-2.535.3190.10716.7710169191219120.9780.12100
2.53-2.695.2920.09618.069562180718070.9830.107100
2.69-2.875.0530.08818.838499168416820.9850.09999.9
2.87-3.14.60.07519.337208157215670.9870.08599.7
3.1-3.45.3840.06922.147834145614550.990.07799.9
3.4-3.85.4970.06622.977190130913080.9910.07399.9
3.8-4.395.3950.06422.996161114211420.9930.07100
4.39-5.385.1710.05622.5350839859830.9940.06299.8
5.38-7.65.0120.05122.1137697527520.9940.057100
7.6-18.875.5950.04123.6321824153900.9980.04594

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Processing

Software
NameVersionClassification
XSCALEdata scaling
PHENIX1.18.2_3874refinement
PDB_EXTRACT3.27data extraction
XDSdata reduction
PHENIXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.7→18.87 Å / Cross valid method: THROUGHOUT / σ(F): 2.39 / Phase error: 22.55 / Stereochemistry target values: TWIN_LSQ_F
RfactorNum. reflection% reflection
Rfree0.2089 2016 5.48 %
Rwork0.1697 34779 -
obs0.1836 36795 99.94 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 74.6 Å2 / Biso mean: 30.9808 Å2 / Biso min: 18.76 Å2
Refinement stepCycle: final / Resolution: 1.7→18.87 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2474 0 58 119 2651
Biso mean--24.04 32.4 -
Num. residues----315
Refine LS restraints NCS
Ens-IDDom-IDAuth asym-IDNumberRefine-IDRmsType
11A884X-RAY DIFFRACTION4.548TORSIONAL
12B884X-RAY DIFFRACTION4.548TORSIONAL
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 14

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
1.7-1.740.28221460.28442497264394
1.74-1.790.22721440.26382467261194
1.79-1.840.26261500.26112461261194
1.84-1.90.28071400.25122514265495
1.9-1.970.24181500.23912483263394
1.97-2.050.2851350.23452496263195
2.05-2.140.25221480.23292453260194
2.14-2.250.2451460.22572498264494
2.25-2.390.21291480.21342473262194
2.4-2.580.23551400.20842488262895
2.58-2.840.24561400.19792488262895
2.84-3.250.20341400.18212501264194
3.25-4.080.22241420.14932473261595
4.08-18.870.19171470.12952487263494
Refinement TLS params.Method: refined / Origin x: 19.9433 Å / Origin y: 12.7498 Å / Origin z: 1.4432 Å
111213212223313233
T0.1672 Å2-0.0294 Å20.0265 Å2-0.1802 Å20.0064 Å2--0.2337 Å2
L1.2345 °2-0.2203 °20.8447 °2-0.2363 °2-0.0264 °2--0.9506 °2
S-0.0148 Å °-0.0614 Å °-0.0102 Å °-0.019 Å °0.0221 Å °-0.0285 Å °-0.0207 Å °-0.0101 Å °-0.0144 Å °
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1allA1 - 167
2X-RAY DIFFRACTION1allB2 - 167
3X-RAY DIFFRACTION1allL1 - 4
4X-RAY DIFFRACTION1allS1 - 119

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