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- PDB-11fb: Structure of GDP-bound KRAS-G12C/Y96C, a Switch-II Pocket Inhibit... -

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Basic information

Entry
Database: PDB / ID: 11fb
TitleStructure of GDP-bound KRAS-G12C/Y96C, 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: 1.5 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 20, 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)19,8884
Polymers19,2991
Non-polymers5903
Water3,531196
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)92.837, 92.837, 119.185
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number155
Space group name H-MH32
Components on special symmetry positions
IDModelComponents
11A-203-

TRS

21A-203-

TRS

31A-340-

HOH

41A-359-

HOH

51A-395-

HOH

61A-413-

HOH

71A-481-

HOH

81A-495-

HOH

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Components

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


Mass: 19298.805 Da / Num. of mol.: 1 / Mutation: G12C,Y96C,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: Chemical ChemComp-TRS / 2-AMINO-2-HYDROXYMETHYL-PROPANE-1,3-DIOL / TRIS BUFFER


Mass: 122.143 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C4H12NO3 / Comment: pH buffer*YM
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 196 / 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: 2.56 Å3/Da / Density % sol: 51.97 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop
Details: 20% v/v glycerol ethoxylate, 3% v/v polyethyleneimine, 0.1 M Tris pH 8.5

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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: 1.5→30.18 Å / Num. obs: 31544 / % possible obs: 99.2 % / Redundancy: 14.9 % / Biso Wilson estimate: 17.2 Å2 / CC1/2: 0.999 / CC star: 1 / Rmerge(I) obs: 0.102 / Rpim(I) all: 0.037 / Rrim(I) all: 0.107 / Net I/σ(I): 16.5
Reflection shellResolution: 1.5→1.59 Å / Redundancy: 10.4 % / Num. unique obs: 5082 / CC1/2: 0.546 / CC star: 0.84 / Rpim(I) all: 0.743 / % possible all: 95.7

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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: 1.5→30.18 Å / SU ML: 0.22 / Cross valid method: THROUGHOUT / σ(F): 1.34 / Phase error: 25.29 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.1997 1574 5 %
Rwork0.1766 29931 -
obs0.1777 31505 99.07 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 84.81 Å2 / Biso mean: 26.4258 Å2 / Biso min: 15.13 Å2
Refinement stepCycle: final / Resolution: 1.5→30.18 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1312 0 37 197 1546
Biso mean--21.03 36.43 -
Num. residues----166
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 11

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
1.5-1.550.43731320.41492530266293
1.55-1.60.33111410.29422670281199
1.6-1.670.28221430.242127112854100
1.67-1.740.24941410.215327172858100
1.74-1.840.24811440.197727232867100
1.84-1.950.22421430.197127212864100
1.95-2.10.2041440.15732737288199
2.1-2.310.16441440.156227362880100
2.31-2.650.17041450.161827592904100
2.65-3.330.20281460.171927702916100
3.33-30.180.17131510.155728573008100
Refinement TLS params.Method: refined / Origin x: -26.7507 Å / Origin y: 18.1123 Å / Origin z: 8.0352 Å
111213212223313233
T0.1548 Å2-0.0026 Å2-0.0013 Å2-0.1506 Å2-0.0049 Å2--0.2747 Å2
L1.2179 °2-0.2138 °2-0.0757 °2-0.5271 °2-0.0658 °2--0.7276 °2
S0.0122 Å °0.0891 Å °0.0062 Å °-0.0659 Å °-0.0027 Å °-0.0156 Å °0.0064 Å °0.0138 Å °-0.0114 Å °
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1allA0 - 202
2X-RAY DIFFRACTION1allB1 - 196
3X-RAY DIFFRACTION1allC1

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