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- PDB-8x6r: KRasG12C in complex with inhibitor -

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Basic information

Entry
Database: PDB / ID: 8x6r
TitleKRasG12C in complex with inhibitor
ComponentsIsoform 2B of GTPase KRas
KeywordsHYDROLASE/INHIBITOR / GTP-binding / HYDROLASE-INHIBITOR COMPLEX
Function / homologysmall monomeric GTPase / Ca2+ pathway / GUANOSINE-5'-DIPHOSPHATE / Chem-Y9D / Isoform 2B of GTPase KRas
Function and homology information
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.85 Å
AuthorsAmano, Y. / Tateishi, Y.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Bioorg.Med.Chem. / Year: 2023
Title: Discovery of ASP6918, a KRAS G12C inhibitor: Synthesis and structure-activity relationships of 1-{2,7-diazaspiro[3.5]non-2-yl}prop-2-en-1-one derivatives as covalent inhibitors with good ...Title: Discovery of ASP6918, a KRAS G12C inhibitor: Synthesis and structure-activity relationships of 1-{2,7-diazaspiro[3.5]non-2-yl}prop-2-en-1-one derivatives as covalent inhibitors with good potency and oral activity for the treatment of solid tumors.
Authors: Imaizumi, T. / Shimada, I. / Satake, Y. / Yamaki, S. / Koike, T. / Nigawara, T. / Kaneko, O. / Amano, Y. / Mori, K. / Yamanaka, Y. / Nakayama, A. / Nishizono, Y. / Shimazaki, M. / Nagashima, T. / Kuramoto, K.
History
DepositionNov 21, 2023Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Jan 17, 2024Provider: 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: Isoform 2B of GTPase KRas
D: Isoform 2B of GTPase KRas
E: Isoform 2B of GTPase KRas
F: Isoform 2B of GTPase KRas
hetero molecules


Theoretical massNumber of molelcules
Total (without water)122,70124
Polymers116,1536
Non-polymers6,54818
Water4,558253
1
A: Isoform 2B of GTPase KRas
hetero molecules


Theoretical massNumber of molelcules
Total (without water)20,4504
Polymers19,3591
Non-polymers1,0913
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area900 Å2
ΔGint-19 kcal/mol
Surface area7920 Å2
MethodPISA
2
B: Isoform 2B of GTPase KRas
hetero molecules


Theoretical massNumber of molelcules
Total (without water)20,4504
Polymers19,3591
Non-polymers1,0913
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area870 Å2
ΔGint-18 kcal/mol
Surface area7890 Å2
MethodPISA
3
C: Isoform 2B of GTPase KRas
hetero molecules


Theoretical massNumber of molelcules
Total (without water)20,4504
Polymers19,3591
Non-polymers1,0913
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area890 Å2
ΔGint-19 kcal/mol
Surface area7970 Å2
MethodPISA
4
D: Isoform 2B of GTPase KRas
hetero molecules


Theoretical massNumber of molelcules
Total (without water)20,4504
Polymers19,3591
Non-polymers1,0913
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area880 Å2
ΔGint-19 kcal/mol
Surface area7910 Å2
MethodPISA
5
E: Isoform 2B of GTPase KRas
hetero molecules


Theoretical massNumber of molelcules
Total (without water)20,4504
Polymers19,3591
Non-polymers1,0913
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area890 Å2
ΔGint-19 kcal/mol
Surface area7830 Å2
MethodPISA
6
F: Isoform 2B of GTPase KRas
hetero molecules


Theoretical massNumber of molelcules
Total (without water)20,4504
Polymers19,3591
Non-polymers1,0913
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area880 Å2
ΔGint-19 kcal/mol
Surface area7870 Å2
MethodPISA
Unit cell
Length a, b, c (Å)67.525, 94.909, 96.199
Angle α, β, γ (deg.)90.00, 91.11, 90.00
Int Tables number4
Space group name H-MP1211

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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.: 6
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.: 6 / 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.: 6 / Source method: obtained synthetically / Formula: Mg
#4: Chemical
ChemComp-Y9D / 1-[7-[6-ethenyl-8-ethoxy-7-(5-methyl-1~{H}-indazol-4-yl)-2-(1-methylpiperidin-4-yl)oxy-quinazolin-4-yl]-2,7-diazaspiro[3.5]nonan-2-yl]propan-1-one


Mass: 623.788 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: C36H45N7O3 / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 253 / 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: 2.65 Å3/Da / Density % sol: 53.64 %
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: BL-5A / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Feb 9, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.85→50 Å / Num. obs: 103763 / % possible obs: 99.9 % / Redundancy: 3.4 % / Rrim(I) all: 0.075 / Net I/σ(I): 5.2
Reflection shellResolution: 1.85→1.88 Å / Redundancy: 3.3 % / Rmerge(I) obs: 0.482 / Num. unique obs: 5168 / CC1/2: 0.807 / CC star: 0.945 / Rpim(I) all: 0.309 / Rrim(I) all: 0.574 / Χ2: 0.505 / % possible all: 99.8

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Processing

Software
NameVersionClassification
REFMAC5.8.0158refinement
HKL-2000data scaling
HKL-2000data reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.85→50 Å / Cor.coef. Fo:Fc: 0.938 / Cor.coef. Fo:Fc free: 0.913 / SU B: 4.539 / SU ML: 0.134 / Cross valid method: THROUGHOUT / ESU R: 0.173 / ESU R Free: 0.166 / Stereochemistry target values: MAXIMUM LIKELIHOOD
RfactorNum. reflection% reflectionSelection details
Rfree0.29936 5079 4.9 %RANDOM
Rwork0.25257 ---
obs0.2548 98657 99.59 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 28.568 Å2
Baniso -1Baniso -2Baniso -3
1-0 Å20 Å20.01 Å2
2---0 Å2-0 Å2
3---0 Å2
Refinement stepCycle: LAST / Resolution: 1.85→50 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7872 0 450 253 8575
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0150.0198484
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.9422.02811508
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.55972
X-RAY DIFFRACTIONr_dihedral_angle_2_deg40.7824.478402
X-RAY DIFFRACTIONr_dihedral_angle_3_deg18.585151482
X-RAY DIFFRACTIONr_dihedral_angle_4_deg21.0911560
X-RAY DIFFRACTIONr_chiral_restr0.1140.21248
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.026672
X-RAY DIFFRACTIONr_gen_planes_other
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_it2.2072.6483924
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it3.3553.954884
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it2.5873.0024560
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other
X-RAY DIFFRACTIONr_long_range_B_refined6.02236.44813162
X-RAY DIFFRACTIONr_long_range_B_other
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.85→1.894 Å
RfactorNum. reflection% reflection
Rfree0.355 331 -
Rwork0.336 6990 -
obs--95.7 %

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