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- PDB-11gh: Structure of GMPPNP-bound KRAS-G12C/Y96D, a Switch-II Pocket Inhi... -

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Basic information

Entry
Database: PDB / ID: 11gh
TitleStructure of GMPPNP-bound KRAS-G12C/Y96D, a Switch-II Pocket Inhibitor Resistance Mutant, in Complex with the RAF1 RBD-CRD
Components
  • GTPase KRas
  • RAF proto-oncogene serine/threonine-protein kinase
KeywordsSIGNALING PROTEIN / RAS / oncogenic mutation / drug resistance
Function / homology
Function and homology information


regulation of Rho protein signal transduction / SHOC2 M1731 mutant abolishes MRAS complex function / Gain-of-function MRAS complexes activate RAF signaling / Rap1 signalling / Negative feedback regulation of MAPK pathway / IFNG signaling activates MAPKs / GP1b-IX-V activation signalling / response to mineralocorticoid / GMP binding / ERBB2-ERBB3 signaling pathway ...regulation of Rho protein signal transduction / SHOC2 M1731 mutant abolishes MRAS complex function / Gain-of-function MRAS complexes activate RAF signaling / Rap1 signalling / Negative feedback regulation of MAPK pathway / IFNG signaling activates MAPKs / GP1b-IX-V activation signalling / response to mineralocorticoid / GMP binding / ERBB2-ERBB3 signaling pathway / LRR domain binding / response to gravity / myoblast proliferation / regulation of cell differentiation / pseudopodium / cardiac muscle cell proliferation / neuromuscular junction development / Signaling by RAS GAP mutants / Signaling by RAS GTPase mutants / Activation of RAS in B cells / GTPase complex / positive regulation of peptidyl-serine phosphorylation / RAS signaling downstream of NF1 loss-of-function variants / RUNX3 regulates p14-ARF / MAP kinase kinase kinase activity / protein phosphatase type 1 complex / type II interferon-mediated signaling pathway / SOS-mediated signalling / Activated NTRK3 signals through RAS / Activated NTRK2 signals through RAS / Schwann cell development / SHC1 events in ERBB4 signaling / Signalling to RAS / negative regulation of programmed cell death / serine/threonine protein kinase complex / negative regulation of protein-containing complex assembly / 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 / myelination / 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 / insulin-like growth factor receptor signaling pathway / 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 / adenylate cyclase activator activity / wound healing / 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 / insulin receptor signaling pathway / cytokine-mediated signaling pathway / Stimuli-sensing channels
Similarity search - Function
Raf-like Ras-binding domain / Raf-like Ras-binding / Ras-binding domain (RBD) profile. / Raf-like Ras-binding domain / Diacylglycerol/phorbol-ester binding / Phorbol esters/diacylglycerol binding domain (C1 domain) / : / Zinc finger phorbol-ester/DAG-type signature. / Zinc finger phorbol-ester/DAG-type profile. / Protein kinase C conserved region 1 (C1) domains (Cysteine-rich domains) ...Raf-like Ras-binding domain / Raf-like Ras-binding / Ras-binding domain (RBD) profile. / Raf-like Ras-binding domain / Diacylglycerol/phorbol-ester binding / Phorbol esters/diacylglycerol binding domain (C1 domain) / : / Zinc finger phorbol-ester/DAG-type signature. / Zinc finger phorbol-ester/DAG-type profile. / Protein kinase C conserved region 1 (C1) domains (Cysteine-rich domains) / Protein kinase C-like, phorbol ester/diacylglycerol-binding domain / C1-like domain superfamily / 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 / Protein tyrosine and serine/threonine kinase / Serine-threonine/tyrosine-protein kinase, catalytic domain / Ubiquitin-like domain superfamily / Serine/threonine-protein kinase, active site / Serine/Threonine protein kinases active-site signature. / Serine/Threonine protein kinases, catalytic domain / Protein kinase, ATP binding site / Protein kinases ATP-binding region signature. / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
PHOSPHOAMINOPHOSPHONIC ACID-GUANYLATE ESTER / GTPase KRas / RAF proto-oncogene serine/threonine-protein kinase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.5 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 22, 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

Downloads & links

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Assembly

Deposited unit
A: GTPase KRas
B: RAF proto-oncogene serine/threonine-protein kinase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,9346
Polymers35,2562
Non-polymers6774
Water1,26170
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3390 Å2
ΔGint-15 kcal/mol
Surface area14710 Å2
MethodPISA
Unit cell
Length a, b, c (Å)133.419, 133.419, 89.928
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number177
Space group name H-MP622

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Components

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Protein , 2 types, 2 molecules AB

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


Mass: 19310.750 Da / Num. of mol.: 1 / Mutation: G12C,Y96D,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: Protein RAF proto-oncogene serine/threonine-protein kinase / Proto-oncogene c-RAF / cRaf / Raf-1


Mass: 15945.492 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: RAF1, RAF / Production host: Escherichia coli (E. coli)
References: UniProt: P04049, non-specific serine/threonine protein kinase

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Non-polymers , 4 types, 74 molecules

#3: Chemical ChemComp-GNP / PHOSPHOAMINOPHOSPHONIC ACID-GUANYLATE ESTER


Mass: 522.196 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C10H17N6O13P3 / Feature type: SUBJECT OF INVESTIGATION
Comment: GppNHp, GMPPNP, energy-carrying molecule analogue*YM
#4: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Mg
#5: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Zn
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 70 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestY
Has protein modificationY

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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: 3.28 Å3/Da / Density % sol: 62.46 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop
Details: 15% v/v PEG 400, 80 mM magnesium acetate, 50 mM sodium cacodylate pH 6.5

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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: Nov 12, 2025
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9791 Å / Relative weight: 1
ReflectionResolution: 2.5→48.61 Å / Num. obs: 16875 / % possible obs: 98.6 % / Redundancy: 34.7 % / Biso Wilson estimate: 63.86 Å2 / CC1/2: 0.999 / CC star: 1 / Rmerge(I) obs: 0.232 / Rpim(I) all: 0.04 / Rrim(I) all: 0.235 / Net I/σ(I): 12.2
Reflection shellResolution: 2.5→2.63 Å / Mean I/σ(I) obs: 1.2 / Num. unique obs: 2356 / CC1/2: 0.82 / CC star: 0.949 / Rpim(I) all: 0.324 / % possible all: 96

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Processing

Software
NameVersionClassification
XDSdata reduction
XDSdata scaling
EPMR16.07.1phasing
PHENIX1.21.2_5419refinement
PDB_EXTRACT3.28data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.5→48.61 Å / SU ML: 0.45 / Cross valid method: THROUGHOUT / σ(F): 1.25 / Phase error: 27.58 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.259 1012 6 %
Rwork0.2105 15857 -
obs0.213 16869 99.94 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 182.65 Å2 / Biso mean: 73.7088 Å2 / Biso min: 39.02 Å2
Refinement stepCycle: final / Resolution: 2.5→48.61 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2406 0 35 70 2511
Biso mean--70.8 61.17 -
Num. residues----301
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 7 / % reflection obs: 100 %

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all
2.5-2.630.51461410.413722132354
2.63-2.80.3391410.308622102351
2.8-3.010.3551420.275622192361
3.01-3.320.30911430.265322382381
3.32-3.790.25931440.210922542398
3.8-4.780.20851450.16922892434
4.78-48.610.22511560.175524342590
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)
12.21821.07720.13813.8121.05173.8423-0.1523-0.2917-0.03620.15070.1868-0.0858-0.21260.0615-0.03890.53760.09310.1020.49310.00980.511653.793611.306526.1988
25.4836-3.28570.93852.4623-1.04790.66380.23940.2461.88320.20930.3019-0.6257-1.02030.0673-0.50391.12980.0405-0.11250.85260.13871.282653.820928.431529.2105
33.2686-0.0195-0.24384.4224-0.14962.128-0.1652-0.62680.18480.98040.25950.5192-0.2191-0.3113-0.11590.83590.16090.2050.69550.04030.542445.607514.607537.393
46.2266-0.5814-0.45093.6774-1.853.1992-0.1926-0.50370.05820.27510.28070.0067-0.23920.0093-0.06650.63820.03090.03910.4836-0.03940.51866.324917.498618.4351
58.42670.66071.54234.01581.72137.1042-0.03540.39660.8195-0.1699-0.1369-0.3347-0.39410.03470.12930.53740.00660.10570.3514-0.02010.535367.541721.98688.5421
62.49060.2584-0.59862.6703-0.8242.97620.0288-0.0708-0.28510.09980.13980.39920.2409-0.3576-0.1270.5423-0.01290.05420.41490.03060.508552.7122-6.22516.3244
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1(chain A and resid 0:59)A0 - 59
2X-RAY DIFFRACTION2(chain A and resid 60:71)A60 - 71
3X-RAY DIFFRACTION3(chain A and resid 72:168)A72 - 168
4X-RAY DIFFRACTION4(chain B and resid 55:94)B55 - 94
5X-RAY DIFFRACTION5(chain B and resid 95:129)B95 - 129
6X-RAY DIFFRACTION6(chain B and resid 130:188)B130 - 188

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