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- PDB-9n9n: Crystal structure of KRAS(G12C) bound to the cyclic peptide UNC10... -

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Basic information

Entry
Database: PDB / ID: 9n9n
TitleCrystal structure of KRAS(G12C) bound to the cyclic peptide UNC10415730A
Components
  • Isoform 2B of GTPase KRas
  • cyclic peptide UNC10415730A
KeywordsONCOPROTEIN / Small GTPase / HYDROLASE / Cyclic Peptide
Function / homology
Function and homology information


response to mineralocorticoid / GMP binding / negative regulation of epithelial cell differentiation / forebrain astrocyte development / LRR domain binding / epithelial tube branching involved in lung morphogenesis / regulation of synaptic transmission, GABAergic / response to isolation stress / type I pneumocyte differentiation / skeletal muscle cell differentiation ...response to mineralocorticoid / GMP binding / negative regulation of epithelial cell differentiation / forebrain astrocyte development / LRR domain binding / epithelial tube branching involved in lung morphogenesis / regulation of synaptic transmission, GABAergic / response to isolation stress / type I pneumocyte differentiation / skeletal muscle cell differentiation / response to gravity / myoblast proliferation / Rac protein signal transduction / cardiac muscle cell proliferation / Signaling by RAS GAP mutants / Signaling by RAS GTPase mutants / Activation of RAS in B cells / positive regulation of glial cell proliferation / RAS signaling downstream of NF1 loss-of-function variants / RUNX3 regulates p14-ARF / homeostasis of number of cells within a tissue / SOS-mediated signalling / Activated NTRK3 signals through RAS / Activated NTRK2 signals through RAS / SHC1 events in ERBB4 signaling / glial cell proliferation / Signalling to RAS / SHC-related events triggered by IGF1R / Activated NTRK2 signals through FRS2 and FRS3 / Estrogen-stimulated signaling through PRKCZ / positive regulation of Rac protein signal transduction / SHC-mediated cascade:FGFR3 / MET activates RAS signaling / SHC-mediated cascade:FGFR2 / SHC-mediated cascade:FGFR4 / Signaling by PDGFRA transmembrane, juxtamembrane and kinase domain mutants / Signaling by PDGFRA extracellular domain mutants / PTK6 Regulates RHO GTPases, RAS GTPase and MAP kinases / Erythropoietin activates RAS / SHC-mediated cascade:FGFR1 / Signaling by FGFR4 in disease / striated muscle cell differentiation / 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 / Signaling by FGFR3 in disease / FRS-mediated FGFR1 signaling / Tie2 Signaling / protein-membrane adaptor activity / Signaling by FGFR2 in disease / Signaling by FLT3 fusion proteins / GRB2 events in EGFR signaling / SHC1 events in EGFR signaling / FLT3 Signaling / Signaling by FGFR1 in disease / EGFR Transactivation by Gastrin / NCAM signaling for neurite out-growth / CD209 (DC-SIGN) signaling / liver development / Downstream signal transduction / GRB2 events in ERBB2 signaling / 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 / VEGFR2 mediated cell proliferation / small monomeric GTPase / FCERI mediated MAPK activation / regulation of long-term neuronal synaptic plasticity / female pregnancy / Signaling by ERBB2 TMD/JMD mutants / visual learning / Signaling by SCF-KIT / Constitutive Signaling by EGFRvIII / 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 / gene expression / cytoplasmic side of plasma membrane / 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 / RAS processing / Regulation of RAS by GAPs / neuron apoptotic process / positive regulation of cellular senescence / Signaling by BRAF and RAF1 fusions / GDP binding
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)
synthetic construct (others)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.24 Å
AuthorsRossman, K.L.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Cancer Institute (NIH/NCI)1R01CA223495 United States
CitationJournal: To Be Published
Title: Crystal structure of KRAS(G12C) bound to the cyclic peptide UNC10415730A
Authors: Betts, L. / Iskandar, S.E. / Bowers, A.A. / Rossman, K.L.
History
DepositionFeb 11, 2025Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 18, 2026Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Isoform 2B of GTPase KRas
B: Isoform 2B of GTPase KRas
C: cyclic peptide UNC10415730A
D: cyclic peptide UNC10415730A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)43,10911
Polymers41,8984
Non-polymers1,2117
Water5,026279
1
A: Isoform 2B of GTPase KRas
C: cyclic peptide UNC10415730A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)21,5095
Polymers20,9492
Non-polymers5603
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2810 Å2
ΔGint-28 kcal/mol
Surface area8190 Å2
MethodPISA
2
B: Isoform 2B of GTPase KRas
D: cyclic peptide UNC10415730A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)21,6016
Polymers20,9492
Non-polymers6524
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2490 Å2
ΔGint-27 kcal/mol
Surface area8480 Å2
MethodPISA
Unit cell
Length a, b, c (Å)61.501, 73.343, 76.584
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121
Space group name HallP2ac2ab
Symmetry operation#1: x,y,z
#2: x+1/2,-y+1/2,-z
#3: -x,y+1/2,-z+1/2
#4: -x+1/2,-y,z+1/2

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Components

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Protein / Protein/peptide , 2 types, 4 molecules ABCD

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


Mass: 19445.980 Da / Num. of mol.: 2 / Mutation: G12C
Source method: isolated from a genetically manipulated source
Details: KRAS 4B, residues 1-169, N-terminal GA from cloning artifact
Source: (gene. exp.) Homo sapiens (human) / Gene: KRAS, KRAS2, RASK2 / Production host: Escherichia coli (E. coli) / References: UniProt: P01116, small monomeric GTPase
#2: Protein/peptide cyclic peptide UNC10415730A


Mass: 1503.119 Da / Num. of mol.: 2 / Source method: obtained synthetically / Source: (synth.) synthetic construct (others)

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Non-polymers , 4 types, 286 molecules

#3: Chemical ChemComp-GDP / GUANOSINE-5'-DIPHOSPHATE


Type: RNA linking / Mass: 443.201 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C10H15N5O11P2 / Comment: GDP, energy-carrying molecule*YM
#4: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Mg
#5: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C3H8O3
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 279 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestN
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: 2.11 Å3/Da / Density % sol: 41.7 % / Description: rods
Crystal growTemperature: 293.15 K / Method: vapor diffusion, sitting drop / Details: 0.15 M Potassium Bromide, 30 % (w/v) PEG 2000 MME

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 22-ID / Wavelength: 1 Å
DetectorType: RAYONIX MX-300 / Detector: CCD / Date: Apr 8, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.24→38.29 Å / Num. obs: 97900 / % possible obs: 91.07 % / Redundancy: 6.6 % / Biso Wilson estimate: 10.84 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.0676 / Rpim(I) all: 0.0285 / Rrim(I) all: 0.0735 / Net I/σ(I): 13.89
Reflection shellResolution: 1.24→1.29 Å / Rmerge(I) obs: 1.766 / Mean I/σ(I) obs: 1.05 / Num. unique obs: 5556 / CC1/2: 0.567 / Rpim(I) all: 0.752

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Processing

Software
NameVersionClassification
PHENIX1.20.1_4487refinement
XDSdata reduction
SCALEPACKdata scaling
PHASERphasing
Cootmodel building
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.24→38.29 Å / SU ML: 0.1347 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 21.4883
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.1976 1982 2.22 %
Rwork0.1739 87255 -
obs0.1745 89237 91.07 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 15.74 Å2
Refinement stepCycle: LAST / Resolution: 1.24→38.29 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2866 0 96 279 3241
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.01213026
X-RAY DIFFRACTIONf_angle_d2.70534091
X-RAY DIFFRACTIONf_chiral_restr0.0837451
X-RAY DIFFRACTIONf_plane_restr0.0093515
X-RAY DIFFRACTIONf_dihedral_angle_d11.6442448
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.24-1.270.3566850.34413736X-RAY DIFFRACTION55.29
1.27-1.310.35491020.27754471X-RAY DIFFRACTION65.98
1.31-1.350.28351320.26465258X-RAY DIFFRACTION77.74
1.35-1.390.2951290.25635922X-RAY DIFFRACTION87.42
1.39-1.440.28651410.25156300X-RAY DIFFRACTION93.01
1.44-1.50.23221420.22636647X-RAY DIFFRACTION97.54
1.5-1.570.20251620.18166715X-RAY DIFFRACTION99.14
1.57-1.650.18771560.16776742X-RAY DIFFRACTION99.34
1.65-1.750.18991500.16546807X-RAY DIFFRACTION99.41
1.75-1.890.19821550.16386796X-RAY DIFFRACTION99.4
1.89-2.080.16571500.14846860X-RAY DIFFRACTION99.76
2.08-2.380.16251590.14536860X-RAY DIFFRACTION99.93
2.38-2.990.18351580.15636957X-RAY DIFFRACTION99.96
2.99-100.18471610.16217184X-RAY DIFFRACTION99.84

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