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- PDB-8dnk: Crystal structure of human KRAS G12C covalently bound with Taiho ... -

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Basic information

Entry
Database: PDB / ID: 8dnk
TitleCrystal structure of human KRAS G12C covalently bound with Taiho WO2020/085493A1 compound 6
ComponentsIsoform 2B of GTPase KRas
KeywordsSIGNALING PROTEIN / Inhibitor / GTPase
Function / homologysmall monomeric GTPase / Ca2+ pathway / P-loop containing nucleotide triphosphate hydrolases / Rossmann fold / 3-Layer(aba) Sandwich / Alpha Beta / GUANOSINE-5'-DIPHOSPHATE / Chem-U50 / Isoform 2B of GTPase KRas
Function and homology information
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.23 Å
AuthorsMohr, C.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: J.Comput.Aided Mol.Des. / Year: 2022
Title: Modeling receptor flexibility in the structure-based design of KRAS G12C inhibitors.
Authors: Zhu, K. / Li, C. / Wu, K.Y. / Mohr, C. / Li, X. / Lanman, B.
History
DepositionJul 11, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 17, 2022Provider: repository / Type: Initial release
Revision 1.1Oct 5, 2022Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.2Oct 18, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model
Revision 1.3Nov 13, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature / Item: _pdbx_entry_details.has_protein_modification

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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)22,2045
Polymers21,1341
Non-polymers1,0704
Water75742
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)91.181, 91.181, 91.181
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number195
Space group name H-MP23
Components on special symmetry positions
IDModelComponents
11A-442-

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: 21133.867 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 (E. coli) / References: UniProt: P01116-2, small monomeric GTPase

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Non-polymers , 5 types, 46 molecules

#2: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Mg
#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-U50 / 2-{[(5-tert-butyl-6-chloro-1H-indazol-3-yl)amino]methyl}-4-chloro-1-methyl-N-(1-propanoylazetidin-3-yl)-1H-imidazole-5-carboxamide


Mass: 506.428 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C23H29Cl2N7O2 / Feature type: SUBJECT OF INVESTIGATION
#5: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: SO4
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 42 / Source method: isolated from a natural source / Formula: H2O

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Details

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: 2.99 Å3/Da / Density % sol: 58.85 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 8.5 / Details: 0.1 M TRIS pH 8.5, 2.0 M Ammonium sulfate

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.2 / Wavelength: 0.99999 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Dec 18, 2020
RadiationMonochromator: Double-crystal, Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.99999 Å / Relative weight: 1
ReflectionResolution: 2.23→64.48 Å / Num. obs: 12603 / % possible obs: 100 % / Redundancy: 38.4 % / CC1/2: 0.998 / Net I/σ(I): 11.8
Reflection shellResolution: 2.23→2.27 Å / Redundancy: 40.1 % / Mean I/σ(I) obs: 2.4 / Num. unique obs: 627 / CC1/2: 0.757 / % possible all: 100

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Processing

Software
NameVersionClassification
BOSv3data collection
DIALSv1.14.3data reduction
xia2v0.5.902data scaling
PHASERv2.8.3phasing
REFMACv5.8.0267refinement
Cootv0.8.9.1model building
PDB_EXTRACTv3.27data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6OIM

6oim


Resolution: 2.23→30 Å / Cor.coef. Fo:Fc: 0.958 / Cor.coef. Fo:Fc free: 0.922 / SU B: 5.7 / SU ML: 0.134 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.203 / ESU R Free: 0.188 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2354 659 5.2 %RANDOM
Rwork0.1809 ---
obs0.1837 11916 99.88 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 119.75 Å2 / Biso mean: 39.259 Å2 / Biso min: 20.39 Å2
Baniso -1Baniso -2Baniso -3
1-0 Å20 Å20 Å2
2--0 Å20 Å2
3---0 Å2
Refinement stepCycle: final / Resolution: 2.23→30 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1351 0 68 42 1461
Biso mean--42.61 38.08 -
Num. residues----169
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0130.0131459
X-RAY DIFFRACTIONr_bond_other_d0.0010.0181349
X-RAY DIFFRACTIONr_angle_refined_deg1.8511.7191973
X-RAY DIFFRACTIONr_angle_other_deg1.3381.6183075
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.5715170
X-RAY DIFFRACTIONr_dihedral_angle_2_deg37.45522.34681
X-RAY DIFFRACTIONr_dihedral_angle_3_deg17.56915255
X-RAY DIFFRACTIONr_dihedral_angle_4_deg19.9851511
X-RAY DIFFRACTIONr_chiral_restr0.0820.2189
X-RAY DIFFRACTIONr_gen_planes_refined0.0080.021611
X-RAY DIFFRACTIONr_gen_planes_other0.0020.02325
LS refinement shellResolution: 2.231→2.289 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.279 32 -
Rwork0.308 881 -
all-913 -
obs--99.89 %

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