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- PDB-9e9h: Crystal structure of human KRAS G12C covalently bound to DEL tria... -

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Basic information

Entry
Database: PDB / ID: 9e9h
TitleCrystal structure of human KRAS G12C covalently bound to DEL triazine compound 5
ComponentsGTPase KRas
KeywordsSIGNALING PROTEIN / ONCOPROTEIN/INHIBITOR / Inhibitor / GTPase / ONCOPROTEIN-INHIBITOR complex
Function / homology
Function and homology information


GMP binding / response to mineralocorticoid / 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 ...GMP binding / response to mineralocorticoid / 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 / Signaling by PDGFRA transmembrane, juxtamembrane and kinase domain mutants / Signaling by PDGFRA extracellular domain mutants / PTK6 Regulates RHO GTPases, RAS GTPase and MAP kinases / SHC-mediated cascade:FGFR4 / Erythropoietin activates RAS / Signaling by FGFR4 in disease / SHC-mediated cascade:FGFR1 / FRS-mediated FGFR3 signaling / Signaling by CSF3 (G-CSF) / Signaling by FLT3 ITD and TKD mutants / FRS-mediated FGFR2 signaling / FRS-mediated FGFR4 signaling / protein-membrane adaptor activity / Signaling by FGFR3 in disease / p38MAPK events / FRS-mediated FGFR1 signaling / 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 / EGFR Transactivation by Gastrin / Signaling by FGFR1 in disease / NCAM signaling for neurite out-growth / homeostasis of number of cells within a tissue / CD209 (DC-SIGN) signaling / GRB2 events in ERBB2 signaling / Downstream signal transduction / Ras activation upon Ca2+ influx through NMDA receptor / SHC1 events in ERBB2 signaling / Insulin receptor signalling cascade / 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 / RAF activation / liver development / female pregnancy / Signaling by ERBB2 TMD/JMD mutants / regulation of long-term neuronal synaptic plasticity / Signaling by high-kinase activity BRAF mutants / Signaling by SCF-KIT / Constitutive Signaling by EGFRvIII / MAP2K and MAPK activation / Signaling by ERBB2 ECD mutants / visual learning / Signaling by ERBB2 KD Mutants / Signaling by CSF1 (M-CSF) in myeloid cells / RAS processing / Regulation of RAS by GAPs / Negative regulation of MAPK pathway / cytoplasmic side of plasma membrane / cytokine-mediated signaling 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 / Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants / positive regulation of cellular senescence / DAP12 signaling / MAPK cascade
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: 1.65 Å
AuthorsMohr, C.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: J.Med.Chem. / Year: 2025
Title: Identification of Structurally Novel KRAS G12C Inhibitors through Covalent DNA-Encoded Library Screening.
Authors: Huang, D. / Manoni, F. / Sun, Z. / Liu, R. / Allen, J.R. / Banerjee, A. / Cee, V.J. / Eshon, J. / Frohn, M.J. / Kaller, M.R. / Lee, H. / Li, C. / Li, X. / Lopez, P. / Ma, V. / Medina, J.M. / ...Authors: Huang, D. / Manoni, F. / Sun, Z. / Liu, R. / Allen, J.R. / Banerjee, A. / Cee, V.J. / Eshon, J. / Frohn, M.J. / Kaller, M.R. / Lee, H. / Li, C. / Li, X. / Lopez, P. / Ma, V. / Medina, J.M. / Mohr, C. / Mukhina, O.A. / Pickrell, A.J. / Stellwagen, J. / Wu, W. / Zhang, W. / Zhu, K. / Dahal, U.P. / Hu, L.A. / Leavitt, M. / Li, W. / Li, Y. / Ma, Y. / Rex, K. / Saiki, A.Y. / Wang, P. / Sun, Y. / Dai, D. / Tamayo, N.A. / Lanman, B.A.
History
DepositionNov 8, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 26, 2025Provider: repository / Type: Initial release
Revision 1.1Mar 5, 2025Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last

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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)22,0874
Polymers21,0391
Non-polymers1,0483
Water1,67593
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)40.715, 40.715, 341.304
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number179
Space group name H-MP6522
Components on special symmetry positions
IDModelComponents
11A-460-

HOH

21A-488-

HOH

31A-492-

HOH

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Components

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


Mass: 21038.613 Da / Num. of mol.: 1 / Mutation: C51S,C80L,C118S
Source method: isolated from a genetically manipulated source
Details: G12C variant / Source: (gene. exp.) Homo sapiens (human) / Gene: KRAS, KRAS2, RASK2 / Variant: VAR_006839 G12C / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: P01116
#2: Chemical ChemComp-CA / CALCIUM ION


Mass: 40.078 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Ca
#3: Chemical ChemComp-GDP / GUANOSINE-5'-DIPHOSPHATE


Type: RNA linking / Mass: 443.201 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C10H15N5O11P2 / Comment: GDP, energy-carrying molecule*YM
#4: Chemical ChemComp-A1BH6 / (3S)-N,5-dimethyl-3-({4-[3-(morpholin-4-yl)phenyl]-6-(2-propanoyl-2,6-diazaspiro[3.4]octan-6-yl)-1,3,5-triazin-2-yl}amino)hexanamide


Mass: 564.722 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C30H44N8O3 / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 93 / Source method: isolated from a natural source / Formula: H2O
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: 1.94 Å3/Da / Density % sol: 36.62 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 6.5
Details: 0.001M calcium chloride, 0.1M MES pH6.5, 30% PEG 4000

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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: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Feb 5, 2020
RadiationMonochromator: Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.65→30 Å / Num. obs: 34847 / % possible obs: 91.9 % / Redundancy: 3.5 % / CC1/2: 0.998 / Rmerge(I) obs: 0.048 / Net I/σ(I): 12.34
Reflection shellResolution: 1.65→1.75 Å / Redundancy: 3.4 % / Rmerge(I) obs: 0.461 / Mean I/σ(I) obs: 1.96 / Num. unique obs: 4184 / CC1/2: 0.861 / % possible all: 68.5

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Processing

Software
NameVersionClassification
XDS2015data reduction
XDS2015data scaling
PHASER2.5.6phasing
REFMAC5.8.0073refinement
Coot0.7.2model building
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.65→30 Å / Cor.coef. Fo:Fc: 0.963 / Cor.coef. Fo:Fc free: 0.942 / SU B: 2.985 / SU ML: 0.099 / Cross valid method: THROUGHOUT / ESU R: 0.125 / ESU R Free: 0.123 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.24989 955 4.8 %RANDOM
Rwork0.20871 ---
obs0.21066 18826 91.27 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 35.819 Å2
Baniso -1Baniso -2Baniso -3
1-1.12 Å20.56 Å2-0 Å2
2--1.12 Å2-0 Å2
3----3.65 Å2
Refinement stepCycle: 1 / Resolution: 1.65→30 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1351 0 70 93 1514
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0050.0191473
X-RAY DIFFRACTIONr_bond_other_d0.0010.021387
X-RAY DIFFRACTIONr_angle_refined_deg1.1762.0211991
X-RAY DIFFRACTIONr_angle_other_deg0.6793.0053141
X-RAY DIFFRACTIONr_dihedral_angle_1_deg4.7755175
X-RAY DIFFRACTIONr_dihedral_angle_2_deg38.65824.11868
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.71115258
X-RAY DIFFRACTIONr_dihedral_angle_4_deg20.1161511
X-RAY DIFFRACTIONr_chiral_restr0.0640.2220
X-RAY DIFFRACTIONr_gen_planes_refined0.0030.021626
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02322
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it1.3823.45689
X-RAY DIFFRACTIONr_mcbond_other1.3763.45684
X-RAY DIFFRACTIONr_mcangle_it2.2685.175856
X-RAY DIFFRACTIONr_mcangle_other2.2675.179857
X-RAY DIFFRACTIONr_scbond_it1.7483.696784
X-RAY DIFFRACTIONr_scbond_other1.7473.695785
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other2.9235.4451131
X-RAY DIFFRACTIONr_long_range_B_refined4.43827.9761711
X-RAY DIFFRACTIONr_long_range_B_other4.39727.7761687
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.653→1.696 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.288 44 -
Rwork0.279 846 -
obs--56.69 %

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