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- PDB-7o83: KRasG12C ligand complex -

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Basic information

Entry
Database: PDB / ID: 7o83
TitleKRasG12C ligand complex
ComponentsV-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog, isoform CRA_b
KeywordsSIGNALING PROTEIN / Inhibitor complex
Function / homology
Function and homology information


endocrine signaling / forebrain astrocyte development / regulation of synaptic transmission, GABAergic / negative regulation of epithelial cell differentiation / epithelial tube branching involved in lung morphogenesis / type I pneumocyte differentiation / Rac protein signal transduction / skeletal muscle cell differentiation / positive regulation of Rac protein signal transduction / glial cell proliferation ...endocrine signaling / forebrain astrocyte development / regulation of synaptic transmission, GABAergic / negative regulation of epithelial cell differentiation / epithelial tube branching involved in lung morphogenesis / type I pneumocyte differentiation / Rac protein signal transduction / skeletal muscle cell differentiation / positive regulation of Rac protein signal transduction / glial cell proliferation / protein-membrane adaptor activity / homeostasis of number of cells within a tissue / positive regulation of glial cell proliferation / striated muscle cell differentiation / regulation of long-term neuronal synaptic plasticity / visual learning / actin cytoskeleton organization / neuron apoptotic process / negative regulation of neuron apoptotic process / GTPase activity / GTP binding / positive regulation of gene expression / membrane
Similarity search - Function
small GTPase Rab1 family profile. / small GTPase Rho family profile. / Small GTPase, Ras-type / small GTPase Ras family profile. / Rho (Ras homology) subfamily of Ras-like small GTPases / Ras subfamily of RAS small GTPases / Small GTPase / Ras family / Rab subfamily of small GTPases / Small GTP-binding protein domain / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
GUANOSINE-5'-DIPHOSPHATE / Chem-V52 / V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog, isoform CRA_b
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.38 Å
AuthorsPhillips, C. / Breed, J.
CitationJournal: J.Med.Chem. / Year: 2022
Title: Discovery of AZD4625, a Covalent Allosteric Inhibitor of the Mutant GTPase KRAS G12C .
Authors: Kettle, J.G. / Bagal, S.K. / Bickerton, S. / Bodnarchuk, M.S. / Boyd, S. / Breed, J. / Carbajo, R.J. / Cassar, D.J. / Chakraborty, A. / Cosulich, S. / Cumming, I. / Davies, M. / Davies, N.L. ...Authors: Kettle, J.G. / Bagal, S.K. / Bickerton, S. / Bodnarchuk, M.S. / Boyd, S. / Breed, J. / Carbajo, R.J. / Cassar, D.J. / Chakraborty, A. / Cosulich, S. / Cumming, I. / Davies, M. / Davies, N.L. / Eatherton, A. / Evans, L. / Feron, L. / Fillery, S. / Gleave, E.S. / Goldberg, F.W. / Hanson, L. / Harlfinger, S. / Howard, M. / Howells, R. / Jackson, A. / Kemmitt, P. / Lamont, G. / Lamont, S. / Lewis, H.J. / Liu, L. / Niedbala, M.J. / Phillips, C. / Polanski, R. / Raubo, P. / Robb, G. / Robinson, D.M. / Ross, S. / Sanders, M.G. / Tonge, M. / Whiteley, R. / Wilkinson, S. / Yang, J. / Zhang, W.
History
DepositionApr 14, 2021Deposition site: PDBE / Processing site: PDBE
Revision 1.0Apr 20, 2022Provider: repository / Type: Initial release
Revision 1.1May 11, 2022Group: Database references / Category: citation / citation_author
Item: _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed ..._citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.identifier_ORCID / _citation_author.name
Revision 1.2May 25, 2022Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.title / _citation_author.identifier_ORCID

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog, isoform CRA_b
B: V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog, isoform CRA_b
hetero molecules


Theoretical massNumber of molelcules
Total (without water)40,0909
Polymers38,1892
Non-polymers1,9017
Water1,53185
1
A: V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog, isoform CRA_b
hetero molecules


Theoretical massNumber of molelcules
Total (without water)20,0655
Polymers19,0941
Non-polymers9714
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog, isoform CRA_b
hetero molecules


Theoretical massNumber of molelcules
Total (without water)20,0254
Polymers19,0941
Non-polymers9303
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)33.509, 39.227, 65.721
Angle α, β, γ (deg.)96.390, 95.010, 103.150
Int Tables number1
Space group name H-MP1

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Components

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Protein , 1 types, 2 molecules AB

#1: Protein V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog, isoform CRA_b


Mass: 19094.490 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: KRAS, hCG_14731 / Production host: Escherichia coli (E. coli) / References: UniProt: A0A024RAV5

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Non-polymers , 5 types, 92 molecules

#2: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Mg
#3: Chemical ChemComp-GDP / GUANOSINE-5'-DIPHOSPHATE / Guanosine diphosphate


Type: RNA linking / Mass: 443.201 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C10H15N5O11P2 / Comment: GDP, energy-carrying molecule*YM
#4: Chemical ChemComp-V52 / 1-[(7S)-11-chloro-12-(5-methyl-1H-indazol-4-yl)-9-oxa-2,5,15,17-tetrazatetracyclo[8.7.1.02,7.014,18]octadeca-1(17),10,12,14(18),15-pentaen-5-yl]prop-2-en-1-one


Mass: 462.931 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C24H23ClN6O2 / Feature type: SUBJECT OF INVESTIGATION
#5: Chemical ChemComp-CA / CALCIUM ION


Mass: 40.078 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Ca
#6: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 85 / 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: 2.18 Å3/Da / Density % sol: 43.62 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / Details: 50mM HEPES, 100mM NaCl, 2mM MgSO4

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I03 / Wavelength: 1 Å
DetectorType: DECTRIS EIGER R 4M / Detector: PIXEL / Date: Mar 1, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.38→38 Å / Num. obs: 11933 / % possible obs: 97.4 % / Redundancy: 2.1 % / Rmerge(I) obs: 0.03 / Net I/σ(I): 10.1
Reflection shellResolution: 2.38→2.44 Å / Rmerge(I) obs: 0.55 / Num. unique obs: 853

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Processing

Software
NameVersionClassification
REFMAC5.8.0238refinement
PDB_EXTRACT3.27data extraction
autoPROCdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: na

Resolution: 2.38→37.85 Å / Cor.coef. Fo:Fc: 0.908 / Cor.coef. Fo:Fc free: 0.835 / SU B: 9.885 / SU ML: 0.234 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 1.616 / ESU R Free: 0.35 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2908 613 4.9 %RANDOM
Rwork0.2226 ---
obs0.2261 11932 97.41 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 66.75 Å2 / Biso mean: 17.425 Å2 / Biso min: 0.5 Å2
Baniso -1Baniso -2Baniso -3
1-0.1 Å2-0.11 Å20.03 Å2
2--0.03 Å2-0.07 Å2
3----0.07 Å2
Refinement stepCycle: final / Resolution: 2.38→37.85 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2671 0 125 85 2881
Biso mean--12.61 17.43 -
Num. residues----335
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.010.0132874
X-RAY DIFFRACTIONr_bond_other_d0.0010.0172601
X-RAY DIFFRACTIONr_angle_refined_deg1.8521.693906
X-RAY DIFFRACTIONr_angle_other_deg1.2381.6216034
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.0825339
X-RAY DIFFRACTIONr_dihedral_angle_2_deg36.93622.564156
X-RAY DIFFRACTIONr_dihedral_angle_3_deg17.50615497
X-RAY DIFFRACTIONr_dihedral_angle_4_deg16.9791520
X-RAY DIFFRACTIONr_chiral_restr0.080.2374
X-RAY DIFFRACTIONr_gen_planes_refined0.0080.023441
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02595
LS refinement shellResolution: 2.38→2.442 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.367 32 -
Rwork0.316 853 -
all-885 -
obs--95.37 %

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