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- PDB-7ycc: KRas G12C in complex with Compound 5c -

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Basic information

Entry
Database: PDB / ID: 7ycc
TitleKRas G12C in complex with Compound 5c
ComponentsIsoform 2B of GTPase KRas
KeywordsONCOPROTEIN/INHIBITOR / ONCOPROTEIN-inhibitor complex
Function / homologysmall monomeric GTPase / Ca2+ pathway / P-loop containing nucleotide triphosphate hydrolases / Rossmann fold / 3-Layer(aba) Sandwich / Alpha Beta / GUANOSINE-5'-DIPHOSPHATE / Chem-IQC / Isoform 2B of GTPase KRas
Function and homology information
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.79 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

Downloads & links

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)61,29412
Polymers58,0773
Non-polymers3,2189
Water3,837213
1
A: Isoform 2B of GTPase KRas
hetero molecules


Theoretical massNumber of molelcules
Total (without water)20,4314
Polymers19,3591
Non-polymers1,0733
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area880 Å2
ΔGint-19 kcal/mol
Surface area7870 Å2
MethodPISA
2
B: Isoform 2B of GTPase KRas
hetero molecules


Theoretical massNumber of molelcules
Total (without water)20,4314
Polymers19,3591
Non-polymers1,0733
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area880 Å2
ΔGint-20 kcal/mol
Surface area7900 Å2
MethodPISA
3
C: Isoform 2B of GTPase KRas
hetero molecules


Theoretical massNumber of molelcules
Total (without water)20,4314
Polymers19,3591
Non-polymers1,0733
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area880 Å2
ΔGint-19 kcal/mol
Surface area7860 Å2
MethodPISA
Unit cell
Length a, b, c (Å)96.268, 94.407, 67.423
Angle α, β, γ (deg.)90.000, 91.490, 90.000
Int Tables number5
Space group name H-MC121
Components on special symmetry positions
IDModelComponents
11A-329-

HOH

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Components

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


Type: RNA linking / Mass: 443.201 Da / Num. of mol.: 3 / 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.: 3 / Source method: obtained synthetically / Formula: Mg
#4: Chemical ChemComp-IQC / 1-[7-[6-chloranyl-8-fluoranyl-7-(5-methyl-1~{H}-indazol-4-yl)-2-[(1-methylpiperidin-4-yl)amino]quinazolin-4-yl]-2,7-diazaspiro[3.5]nonan-2-yl]propan-1-one


Mass: 605.149 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C32H38ClFN8O / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 213 / Source method: isolated from a natural source / Formula: H2O
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: 2.64 Å3/Da / Density % sol: 53.35 %
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: SYNCHROTRON / Site: Photon Factory / Beamline: AR-NE3A / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 270 / Detector: CCD / Date: Nov 4, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.79→50 Å / Num. obs: 53071 / % possible obs: 94.4 % / Redundancy: 3.4 % / Rmerge(I) obs: 0.055 / Rpim(I) all: 0.035 / Rrim(I) all: 0.065 / Χ2: 2.835 / Net I/σ(I): 17.4
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsCC1/2Rpim(I) allRrim(I) allΧ2% possible all
1.8-1.833.30.18324420.9620.1190.2191.285.6
1.83-1.863.60.17624090.9690.1080.2071.45187.1
1.86-1.93.60.18525220.9570.1160.2192.14589.1
1.9-1.943.40.17825060.9330.1180.2142.66690.3
1.94-1.983.50.14326500.970.090.1692.36593.8
1.98-2.033.50.11126670.9810.070.1312.26396
2.03-2.083.30.11926210.9720.080.1442.93394.4
2.08-2.133.40.10127130.980.0650.1212.58796.7
2.13-2.23.20.08727430.9850.0570.1042.58596.8
2.2-2.273.20.08926620.980.0610.1083.07395.7
2.27-2.353.30.07527230.990.0490.0912.79297.3
2.35-2.443.60.07927280.9890.0490.0933.0397.4
2.44-2.553.60.07427300.990.0460.0873.24397.7
2.55-2.693.50.07427710.9890.0470.0883.70197.5
2.69-2.863.50.0727240.9910.0440.0833.71597.3
2.86-3.083.30.06227530.9920.040.0743.80297.3
3.08-3.393.10.05527450.9930.0360.0663.77797.3
3.39-3.883.40.05225750.9940.0330.0623.7892.3
3.88-4.883.40.04325780.9960.0270.0513.16890.3
4.88-503.40.03828090.9960.0240.0452.27597.5

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Processing

Software
NameVersionClassification
HKL-2000data scaling
REFMAC5.8.0257refinement
PDB_EXTRACT3.27data extraction
HKL-2000data reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4L8G

4l8g


Resolution: 1.79→33.72 Å / Cor.coef. Fo:Fc: 0.951 / Cor.coef. Fo:Fc free: 0.926 / SU B: 3.211 / SU ML: 0.101 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.144 / ESU R Free: 0.14 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.255 2709 5.1 %RANDOM
Rwork0.2116 ---
obs0.2139 50356 94.12 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 110.77 Å2 / Biso mean: 35.302 Å2 / Biso min: 14.07 Å2
Baniso -1Baniso -2Baniso -3
1-0.02 Å2-0 Å20 Å2
2---0.01 Å2-0 Å2
3----0.01 Å2
Refinement stepCycle: final / Resolution: 1.79→33.72 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3946 0 216 213 4375
Biso mean--36.3 37.32 -
Num. residues----494
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0090.0124243
X-RAY DIFFRACTIONr_angle_refined_deg2.1881.7315758
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.7355488
X-RAY DIFFRACTIONr_dihedral_angle_2_deg36.40122.707229
X-RAY DIFFRACTIONr_dihedral_angle_3_deg17.4815744
X-RAY DIFFRACTIONr_dihedral_angle_4_deg21.241529
X-RAY DIFFRACTIONr_chiral_restr0.1210.2548
X-RAY DIFFRACTIONr_gen_planes_refined0.0170.023383
LS refinement shellResolution: 1.794→1.841 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.339 164 -
Rwork0.274 3313 -
obs-3477 83.02 %

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