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- PDB-8cx5: Crystal Structure of small molecule alpha,beta-ketoamide 4 covale... -

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Basic information

Entry
Database: PDB / ID: 8cx5
TitleCrystal Structure of small molecule alpha,beta-ketoamide 4 covalently bound to K-Ras(G12R)
ComponentsIsoform 2B of GTPase KRas
KeywordsSIGNALING PROTEIN/INHIBITOR / Inhibitor / SIGNALING PROTEIN / SIGNALING PROTEIN-INHIBITOR complex
Function / homologysmall monomeric GTPase / Ca2+ pathway / GUANOSINE-5'-DIPHOSPHATE / Chem-P7U / PHOSPHATE ION / Isoform 2B of GTPase KRas
Function and homology information
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.72 Å
AuthorsZhang, Z. / Morstein, J. / Ecker, A. / Guiley, K.Z. / Shokat, K.M.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Cancer Institute (NIH/NCI)1R01CA244550 United States
CitationJournal: J.Am.Chem.Soc. / Year: 2022
Title: Chemoselective Covalent Modification of K-Ras(G12R) with a Small Molecule Electrophile.
Authors: Zhang, Z. / Morstein, J. / Ecker, A.K. / Guiley, K.Z. / Shokat, K.M.
History
DepositionMay 19, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 31, 2022Provider: repository / Type: Initial release
Revision 1.1Sep 7, 2022Group: Database references / Category: citation / citation_author
Item: _citation.pdbx_database_id_PubMed / _citation.title ..._citation.pdbx_database_id_PubMed / _citation.title / _citation_author.identifier_ORCID / _citation_author.name
Revision 1.2Sep 14, 2022Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
Revision 1.3Oct 18, 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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)41,34211
Polymers38,8142
Non-polymers2,5289
Water3,693205
1
A: Isoform 2B of GTPase KRas
hetero molecules


Theoretical massNumber of molelcules
Total (without water)20,5654
Polymers19,4071
Non-polymers1,1583
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Isoform 2B of GTPase KRas
hetero molecules


Theoretical massNumber of molelcules
Total (without water)20,7777
Polymers19,4071
Non-polymers1,3716
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)41.210, 65.661, 61.130
Angle α, β, γ (deg.)90.000, 101.850, 90.000
Int Tables number4
Space group name H-MP1211
Space group name HallP2yb
Symmetry operation#1: x,y,z
#2: -x,y+1/2,-z

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Components

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Protein , 1 types, 2 molecules AB

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


Mass: 19406.838 Da / Num. of mol.: 2 / Mutation: G12R, C51S, C80L, C118S
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: KRAS, KRAS2, RASK2 / Production host: Escherichia coli BL21(DE3) (bacteria) / Strain (production host): BL21(DE3) / References: UniProt: P01116-2, small monomeric GTPase

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Non-polymers , 6 types, 214 molecules

#2: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Mg
#3: Chemical ChemComp-P7U / {(2S)-4-[(7P)-7-(8-chloronaphthalen-1-yl)-8-fluoro-2-{[(4R,7as)-tetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-4-yl]-1-[(3S)-2,2,3-trihydroxybutanoyl]piperazin-2-yl}acetonitrile


Mass: 690.164 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C35H37ClFN7O5 / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical ChemComp-GDP / GUANOSINE-5'-DIPHOSPHATE


Type: RNA linking / Mass: 443.201 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C10H15N5O11P2 / Comment: GDP, energy-carrying molecule*YM
#5: Chemical ChemComp-PO4 / PHOSPHATE ION


Mass: 94.971 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: PO4
#6: Chemical ChemComp-NA / SODIUM ION


Mass: 22.990 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Na
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 205 / 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: 2.04 Å3/Da / Density % sol: 39.73 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 6.5 / Details: 0.1 M MES 6.5 30% w/v PEG 4K

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 8.2.1 / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Oct 28, 2021
RadiationMonochromator: M / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.72→65.66 Å / Num. obs: 32559 / % possible obs: 96.3 % / Redundancy: 5.9 % / Biso Wilson estimate: 20.59 Å2 / CC1/2: 0.974 / Rmerge(I) obs: 0.156 / Rpim(I) all: 0.071 / Net I/σ(I): 10.7
Reflection shellResolution: 1.72→1.75 Å / Redundancy: 4.6 % / Rmerge(I) obs: 1.879 / Mean I/σ(I) obs: 1.7 / Num. unique obs: 1640 / CC1/2: 0.417 / Rpim(I) all: 0.992 / % possible all: 92.8

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Processing

Software
NameVersionClassification
PHENIX1.19.2_4158refinement
PHENIX1.19.2_4158refinement
MOSFLMdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6UT0

6ut0


Resolution: 1.72→59.83 Å / SU ML: 0.2354 / Cross valid method: FREE R-VALUE / σ(F): 1.38 / Phase error: 22.3407
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2211 1639 5.07 %
Rwork0.1885 30672 -
obs0.1901 32311 95.31 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 24 Å2
Refinement stepCycle: LAST / Resolution: 1.72→59.83 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2752 0 119 207 3078
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.01112940
X-RAY DIFFRACTIONf_angle_d1.50744007
X-RAY DIFFRACTIONf_chiral_restr0.076437
X-RAY DIFFRACTIONf_plane_restr0.0106497
X-RAY DIFFRACTIONf_dihedral_angle_d19.14661097
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.72-1.770.41511330.3462414X-RAY DIFFRACTION91.62
1.77-1.830.31631160.26462559X-RAY DIFFRACTION94.42
1.83-1.890.23831380.23922509X-RAY DIFFRACTION95.01
1.89-1.970.26921290.212531X-RAY DIFFRACTION93.86
1.97-2.060.26541370.19392561X-RAY DIFFRACTION95.88
2.06-2.170.2241400.20172553X-RAY DIFFRACTION95.36
2.17-2.30.25231360.19882504X-RAY DIFFRACTION94.18
2.3-2.480.22831290.18662584X-RAY DIFFRACTION96.51
2.48-2.730.19661460.1962605X-RAY DIFFRACTION97
2.73-3.130.20751470.18992602X-RAY DIFFRACTION96.86
3.13-3.940.21391500.16512587X-RAY DIFFRACTION96.68
3.94-59.830.17551380.15762663X-RAY DIFFRACTION96.35

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