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- PDB-8dnj: Crystal structure of human KRAS G12C covalently bound with AstraZ... -

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Basic information

Entry
Database: PDB / ID: 8dnj
TitleCrystal structure of human KRAS G12C covalently bound with AstraZeneca WO2020/178282A1 compound 76
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-U4U / Isoform 2B of GTPase KRas
Function and homology information
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.81 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 1.3Oct 16, 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

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)66,09112
Polymers63,4023
Non-polymers2,6899
Water3,585199
1
A: Isoform 2B of GTPase KRas
hetero molecules


Theoretical massNumber of molelcules
Total (without water)22,0304
Polymers21,1341
Non-polymers8963
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Isoform 2B of GTPase KRas
hetero molecules


Theoretical massNumber of molelcules
Total (without water)22,0304
Polymers21,1341
Non-polymers8963
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
C: Isoform 2B of GTPase KRas
hetero molecules


Theoretical massNumber of molelcules
Total (without water)22,0304
Polymers21,1341
Non-polymers8963
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)37.594, 112.162, 57.821
Angle α, β, γ (deg.)90.000, 96.800, 90.000
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: 21133.867 Da / Num. of mol.: 3 / 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
#2: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: Mg
#3: 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
#4: Chemical ChemComp-U4U / 1-[(5S,9P,12aR)-9-(2-chloro-6-hydroxyphenyl)-8-ethynyl-10-fluoro-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepin-2(1H)-yl]propan-1-one


Mass: 428.884 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C23H22ClFN2O3 / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 199 / 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: 1.91 Å3/Da / Density % sol: 35.58 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 6.5
Details: 0.001M MgCl2, 0.1 M MES pH 6.5, 30% PEG 4000, 10% Ethanol

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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: 1.81→112.11 Å / Num. obs: 43236 / % possible obs: 99.8 % / Redundancy: 6.3 % / CC1/2: 0.948 / Net I/σ(I): 4.8
Reflection shellResolution: 1.81→1.84 Å / Redundancy: 5.3 % / Mean I/σ(I) obs: 1.1 / Num. unique obs: 1996 / CC1/2: 0.564 / % possible all: 95.2

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Processing

Software
NameVersionClassification
BOSv3data collection
DIALSv1.14.13data reduction
xia2v0.5.092data 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: 1.81→30 Å / Cor.coef. Fo:Fc: 0.935 / Cor.coef. Fo:Fc free: 0.896 / SU B: 7.927 / SU ML: 0.214 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.193 / ESU R Free: 0.175 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2889 2186 5.1 %RANDOM
Rwork0.2392 ---
obs0.2418 40836 99.46 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 70.31 Å2 / Biso mean: 25.834 Å2 / Biso min: 12.54 Å2
Baniso -1Baniso -2Baniso -3
1--1.32 Å20 Å2-0.21 Å2
2---2.2 Å2-0 Å2
3---3.47 Å2
Refinement stepCycle: final / Resolution: 1.81→30 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4034 0 177 199 4410
Biso mean--21.04 29 -
Num. residues----506
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0030.0134316
X-RAY DIFFRACTIONr_bond_other_d0.0020.0153980
X-RAY DIFFRACTIONr_angle_refined_deg1.3231.7165826
X-RAY DIFFRACTIONr_angle_other_deg1.1341.6129091
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.5925505
X-RAY DIFFRACTIONr_dihedral_angle_2_deg37.57122.489237
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.62615751
X-RAY DIFFRACTIONr_dihedral_angle_4_deg14.2931531
X-RAY DIFFRACTIONr_chiral_restr0.0490.2562
X-RAY DIFFRACTIONr_gen_planes_refined0.0030.024770
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02953
LS refinement shellResolution: 1.81→1.857 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.387 155 -
Rwork0.361 2960 -
all-3115 -
obs--97.86 %

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