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- PDB-7yce: KRas G12C in complex with Compound 7b -

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Basic information

Entry
Database: PDB / ID: 7yce
TitleKRas G12C in complex with Compound 7b
ComponentsIsoform 2B of GTPase KRas
KeywordsONCOPROTEIN/inhibitor / ONCOPROTEIN-inhibitor complex
Function / homologysmall monomeric GTPase / Ca2+ pathway / GUANOSINE-5'-DIPHOSPHATE / Chem-IQN / Isoform 2B of GTPase KRas
Function and homology information
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 1.8 Å
AuthorsAmano, Y.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Bioorg.Med.Chem. / Year: 2022
Title: Discovery and biological evaluation of 1-{2,7-diazaspiro[3.5]nonan-2-yl}prop-2-en-1-one derivatives as covalent inhibitors of KRAS G12C with favorable metabolic stability and anti-tumor activity.
Authors: Imaizumi, T. / Akaiwa, M. / Abe, T. / Nigawara, T. / Koike, T. / Satake, Y. / Watanabe, K. / Kaneko, O. / Amano, Y. / Mori, K. / Yamanaka, Y. / Nagashima, T. / Shimazaki, M. / Kuramoto, K.
History
DepositionJul 1, 2022Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Aug 10, 2022Provider: repository / Type: Initial release
Revision 1.1Aug 17, 2022Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_last ..._citation.journal_volume / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.2Nov 29, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Isoform 2B of GTPase KRas
hetero molecules


Theoretical massNumber of molelcules
Total (without water)20,5435
Polymers19,3591
Non-polymers1,1844
Water1,71195
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area880 Å2
ΔGint-19 kcal/mol
Surface area8280 Å2
MethodPISA
Unit cell
Length a, b, c (Å)94.809, 94.809, 119.410
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-392-

HOH

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Components

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Protein , 1 types, 1 molecules A

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


Mass: 19358.836 Da / Num. of mol.: 1 / Mutation: G12C, 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: P01116-2, small monomeric GTPase

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Non-polymers , 5 types, 99 molecules

#2: 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
#3: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Mg
#4: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: SO4
#5: Chemical ChemComp-IQN / 1-[7-[6-chloranyl-2-(1-ethylpiperidin-4-yl)oxy-8-fluoranyl-7-(5-methyl-1~{H}-indazol-4-yl)quinazolin-4-yl]-2,7-diazaspiro[3.5]nonan-2-yl]propan-1-one


Mass: 620.160 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C33H39ClFN7O2 / Feature type: SUBJECT OF INVESTIGATION
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 95 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestY

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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: 2.67 Å3/Da / Density % sol: 53.89 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 6.5 / Details: MES, ammonium sulfate, PEG550MME

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Data collection

DiffractionMean temperature: 90 K / Serial crystal experiment: N
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU FR-E+ SUPERBRIGHT / Wavelength: 1.5418 Å
DetectorType: RIGAKU HyPix-6000HE / Detector: PIXEL / Date: Jun 9, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 1.8→22.94 Å / Num. obs: 17961 / % possible obs: 92.9 % / Redundancy: 8.7 % / CC1/2: 0.987 / Rmerge(I) obs: 0.068 / Rpim(I) all: 0.025 / Rrim(I) all: 0.073 / Net I/σ(I): 18.7
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. measured allNum. unique obsCC1/2Rpim(I) allRrim(I) allNet I/σ(I) obs% possible all
1.8-1.8410.30.1851194311630.9910.060.1955.3100
9-22.936.30.02210711700.9990.010.02439.594.4

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Processing

Software
NameVersionClassification
Aimless0.7.4data scaling
REFMAC5.8.0257refinement
PDB_EXTRACT3.27data extraction
CrysalisProdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4L8G

4l8g


Resolution: 1.8→22.94 Å / Cor.coef. Fo:Fc: 0.88 / Cor.coef. Fo:Fc free: 0.872 / SU B: 4.501 / SU ML: 0.132 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.193 / ESU R Free: 0.164 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.291 933 5.2 %RANDOM
Rwork0.2737 ---
obs0.2747 16941 92.25 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 97.79 Å2 / Biso mean: 25.494 Å2 / Biso min: 8.49 Å2
Baniso -1Baniso -2Baniso -3
1--0.47 Å2-0.23 Å2-0 Å2
2---0.47 Å2-0 Å2
3---1.51 Å2
Refinement stepCycle: final / Resolution: 1.8→22.94 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1345 0 78 95 1518
Biso mean--24.37 29.56 -
Num. residues----169
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0070.0121450
X-RAY DIFFRACTIONr_angle_refined_deg1.8081.7331969
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.2495168
X-RAY DIFFRACTIONr_dihedral_angle_2_deg36.5822.69278
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.86215253
X-RAY DIFFRACTIONr_dihedral_angle_4_deg20.0661510
X-RAY DIFFRACTIONr_chiral_restr0.1230.2187
X-RAY DIFFRACTIONr_gen_planes_refined0.0080.021144
LS refinement shellResolution: 1.8→1.847 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.279 75 -
Rwork0.224 1337 -
all-1412 -
obs--99.37 %

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