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- PDB-11ft: Structure of GDP-bound KRAS-G12C/Q99L, a Switch-II Pocket Inhibit... -

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Basic information

Entry
Database: PDB / ID: 11ft
TitleStructure of GDP-bound KRAS-G12C/Q99L, a Switch-II Pocket Inhibitor Resistance Mutant
ComponentsGTPase KRas
KeywordsSIGNALING PROTEIN / RAS / oncogenic mutation / drug resistance
Function / homology
Function and homology information


response to mineralocorticoid / GMP binding / LRR domain binding / response to gravity / myoblast proliferation / cardiac muscle cell proliferation / Signaling by RAS GAP mutants / Signaling by RAS GTPase mutants / Activation of RAS in B cells / GTPase complex ...response to mineralocorticoid / GMP binding / LRR domain binding / response to gravity / myoblast proliferation / cardiac muscle cell proliferation / Signaling by RAS GAP mutants / Signaling by RAS GTPase mutants / Activation of RAS in B cells / GTPase complex / RAS signaling downstream of NF1 loss-of-function variants / RUNX3 regulates p14-ARF / protein phosphatase type 1 complex / SOS-mediated signalling / Activated NTRK3 signals through RAS / Activated NTRK2 signals through RAS / SHC1 events in ERBB4 signaling / Signalling to RAS / negative regulation of programmed cell death / serine/threonine protein kinase complex / SHC-related events triggered by IGF1R / Activated NTRK2 signals through FRS2 and FRS3 / Estrogen-stimulated signaling through PRKCZ / SHC-mediated cascade:FGFR3 / MET activates RAS signaling / positive regulation of Ras protein signal transduction / response to isolation stress / SHC-mediated cascade:FGFR2 / SHC-mediated cascade:FGFR4 / PTK6 Regulates RHO GTPases, RAS GTPase and MAP kinases / Signaling by PDGFRA transmembrane, juxtamembrane and kinase domain mutants / Signaling by PDGFRA extracellular domain mutants / Erythropoietin activates RAS / SHC-mediated cascade:FGFR1 / Signaling by FGFR4 in disease / Signaling by CSF3 (G-CSF) / FRS-mediated FGFR3 signaling / 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 / Tie2 Signaling / Signaling by FGFR2 in disease / GRB2 events in EGFR signaling / Signaling by FLT3 fusion proteins / SHC1 events in EGFR signaling / FLT3 Signaling / EGFR Transactivation by Gastrin / Signaling by FGFR1 in disease / NCAM signaling for neurite out-growth / liver development / CD209 (DC-SIGN) signaling / positive regulation of TOR signaling / GRB2 events in ERBB2 signaling / Downstream signal transduction / response to glucocorticoid / Insulin receptor signalling cascade / SHC1 events in ERBB2 signaling / Constitutive Signaling by Overexpressed ERBB2 / Ras activation upon Ca2+ influx through NMDA receptor / Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants / canonical NF-kappaB signal transduction / VEGFR2 mediated cell proliferation / small monomeric GTPase / endomembrane system / FCERI mediated MAPK activation / female pregnancy / Signaling by ERBB2 TMD/JMD mutants / Constitutive Signaling by EGFRvIII / Signaling by SCF-KIT / RAF activation / Signaling by high-kinase activity BRAF mutants / Signaling by ERBB2 ECD mutants / MAP2K and MAPK activation / Signaling by ERBB2 KD Mutants / cytokine-mediated signaling pathway / Signaling by RAF1 mutants / Signaling by CSF1 (M-CSF) in myeloid cells / Signaling by moderate kinase activity BRAF mutants / Paradoxical activation of RAF signaling by kinase inactive BRAF / Signaling downstream of RAS mutants / MAPK cascade / Negative regulation of MAPK pathway / Regulation of RAS by GAPs / RAS processing / positive regulation of cellular senescence / Signaling by BRAF and RAF1 fusions / GDP binding / DAP12 signaling / Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants / regulation of cell population proliferation / RAF/MAP kinase cascade / G protein activity / Ca2+ pathway / cytoplasmic side of plasma membrane / Ras protein signal transduction / positive regulation of MAPK cascade / mitochondrial outer membrane
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: 1.16 Å
AuthorsWhitley, M.J. / Simanshu, D.K.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Cancer Institute (NIH/NCI)75N91019D00024 United States
CitationJournal: Nat Commun / Year: 2026
Title: Structural mechanisms underlying resistance to Switch-II pocket inhibitors in KRAS
Authors: Whitley, M.J. / Dyba, M. / Chakrabarti, M. / Smith, B.P. / Chan, A.H. / Denson, J.P. / Messing, S.A. / Lin, K. / Cornilescu, G. / Balius, T.E. / Nissley, D.V. / McCormick, F. / Maciag, A.E. / Simanshu, D.K.
History
DepositionFeb 21, 2026Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 7, 2026Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: GTPase KRas
hetero molecules


Theoretical massNumber of molelcules
Total (without water)19,8113
Polymers19,3441
Non-polymers4682
Water3,603200
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)39.207, 40.567, 92.163
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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Components

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


Mass: 19343.865 Da / Num. of mol.: 1 / Mutation: G12C,Q99L,C118S
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.: 1 / Source method: obtained synthetically / Formula: Mg
#3: Chemical ChemComp-GDP / GUANOSINE-5'-DIPHOSPHATE


Type: RNA linking / Mass: 443.201 Da / Num. of mol.: 1 / 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.: 200 / 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: 1.89 Å3/Da / Density % sol: 35.07 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / Details: 30% w/v PEG MME 5000, 0.1 M sodium acetate pH 4.5

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRL / Beamline: BL12-1 / Wavelength: 0.9795 Å
DetectorType: DECTRIS EIGER2 XE 16M / Detector: PIXEL / Date: Mar 26, 2025
RadiationMonochromator: Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9795 Å / Relative weight: 1
ReflectionResolution: 1.16→28.19 Å / Num. obs: 49307 / % possible obs: 95.3 % / Redundancy: 10.9 % / Biso Wilson estimate: 11.85 Å2 / CC1/2: 0.999 / CC star: 1 / Rmerge(I) obs: 0.065 / Rpim(I) all: 0.02 / Rrim(I) all: 0.068 / Net I/σ(I): 18.5
Reflection shellResolution: 1.16→1.18 Å / Redundancy: 6.3 % / Rmerge(I) obs: 0.41 / Mean I/σ(I) obs: 4.2 / Num. unique obs: 1762 / CC1/2: 0.941 / CC star: 0.985 / Rpim(I) all: 0.1756 / Rrim(I) all: 0.447 / % possible all: 62.2

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Processing

Software
NameVersionClassification
XDSdata reduction
XDSdata scaling
MoRDaphasing
PHENIX1.21.2_5419refinement
PDB_EXTRACT3.28data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.16→28.19 Å / SU ML: 0.07 / Cross valid method: THROUGHOUT / σ(F): 1.39 / Phase error: 14.93 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.1764 2466 5 %
Rwork0.144 46839 -
obs0.1456 49305 95.31 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 88.62 Å2 / Biso mean: 17.0343 Å2 / Biso min: 7.48 Å2
Refinement stepCycle: final / Resolution: 1.16→28.19 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1356 0 29 200 1585
Biso mean--12.52 27.32 -
Num. residues----170
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 18

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
1.16-1.180.1778880.14171674176262
1.18-1.210.17121060.11992001210775
1.21-1.230.1521230.11782337246087
1.23-1.260.16391360.11272587272395
1.26-1.290.16051380.10512628276699
1.29-1.330.12711420.105526892831100
1.33-1.370.14961410.108726912832100
1.37-1.410.17331440.10827282872100
1.41-1.460.13551420.106327062848100
1.46-1.520.13311430.108927032846100
1.52-1.590.15111420.115527082850100
1.59-1.670.13791430.119427112854100
1.67-1.780.19111440.138527402884100
1.78-1.910.19961430.151127132856100
1.92-2.110.17981440.1422740288499
2.11-2.410.18191460.15427642910100
2.41-3.040.19331470.177927972944100
3.04-28.190.18611540.15512922307699

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