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- PDB-8b78: KRasG12C ligand complex -

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Basic information

Entry
Database: PDB / ID: 8b78
TitleKRasG12C ligand complex
ComponentsGTPase KRas
KeywordsSIGNALING PROTEIN / INHIBITOR COMPLEX
Function / homology
Function and homology information


forebrain astrocyte development / negative regulation of epithelial cell differentiation / regulation of synaptic transmission, GABAergic / 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 / Signaling by RAS GAP mutants / Signaling by RAS GTPase mutants ...forebrain astrocyte development / negative regulation of epithelial cell differentiation / regulation of synaptic transmission, GABAergic / 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 / Signaling by RAS GAP mutants / Signaling by RAS GTPase mutants / Activation of RAS in B cells / RAS signaling downstream of NF1 loss-of-function variants / RUNX3 regulates p14-ARF / SOS-mediated signalling / Activated NTRK3 signals through RAS / Activated NTRK2 signals through RAS / SHC1 events in ERBB4 signaling / Signalling to RAS / glial cell proliferation / SHC-related events triggered by IGF1R / Activated NTRK2 signals through FRS2 and FRS3 / Estrogen-stimulated signaling through PRKCZ / SHC-mediated cascade:FGFR3 / MET activates RAS signaling / PTK6 Regulates RHO GTPases, RAS GTPase and MAP kinases / Signaling by PDGFRA transmembrane, juxtamembrane and kinase domain mutants / Signaling by PDGFRA extracellular domain mutants / SHC-mediated cascade:FGFR2 / SHC-mediated cascade:FGFR4 / Signaling by FGFR4 in disease / SHC-mediated cascade:FGFR1 / Erythropoietin activates RAS / protein-membrane adaptor activity / FRS-mediated FGFR3 signaling / Signaling by CSF3 (G-CSF) / positive regulation of glial cell proliferation / Signaling by FLT3 ITD and TKD mutants / homeostasis of number of cells within a tissue / FRS-mediated FGFR2 signaling / FRS-mediated FGFR4 signaling / Signaling by FGFR3 in disease / FRS-mediated FGFR1 signaling / p38MAPK events / Tie2 Signaling / Signaling by FGFR2 in disease / striated muscle cell differentiation / GRB2 events in EGFR signaling / SHC1 events in EGFR signaling / EGFR Transactivation by Gastrin / Signaling by FLT3 fusion proteins / FLT3 Signaling / Signaling by FGFR1 in disease / Ras activation upon Ca2+ influx through NMDA receptor / GRB2 events in ERBB2 signaling / NCAM signaling for neurite out-growth / CD209 (DC-SIGN) signaling / SHC1 events in ERBB2 signaling / Downstream signal transduction / Constitutive Signaling by Overexpressed ERBB2 / Insulin receptor signalling cascade / small monomeric GTPase / G protein activity / Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants / VEGFR2 mediated cell proliferation / FCERI mediated MAPK activation / Signaling by ERBB2 TMD/JMD mutants / regulation of long-term neuronal synaptic plasticity / RAF activation / Signaling by high-kinase activity BRAF mutants / Constitutive Signaling by EGFRvIII / visual learning / MAP2K and MAPK activation / Signaling by ERBB2 ECD mutants / Signaling by ERBB2 KD Mutants / Signaling by SCF-KIT / cytoplasmic side of plasma membrane / Regulation of RAS by GAPs / Negative regulation of MAPK pathway / RAS processing / Signaling by RAF1 mutants / GDP binding / Signaling by moderate kinase activity BRAF mutants / Paradoxical activation of RAF signaling by kinase inactive BRAF / Signaling downstream of RAS mutants / Signaling by CSF1 (M-CSF) in myeloid cells / MAPK cascade / Signaling by BRAF and RAF1 fusions / DAP12 signaling / Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants / Ca2+ pathway / gene expression / actin cytoskeleton organization / RAF/MAP kinase cascade / neuron apoptotic process / mitochondrial outer membrane / negative regulation of neuron apoptotic process / Ras protein signal transduction / positive regulation of protein phosphorylation / Golgi membrane / focal adhesion
Similarity search - Function
Small GTPase, Ras-type / small GTPase Ras family profile. / Ran (Ras-related nuclear proteins) /TC4 subfamily of small GTPases / 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-PUO / GTPase KRas
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.11 Å
AuthorsPhillips, C. / Breed, J.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: J.Med.Chem. / Year: 2023
Title: Discovery of AZD4747, a Potent and Selective Inhibitor of Mutant GTPase KRAS G12C with Demonstrable CNS Penetration.
Authors: Kettle, J.G. / Bagal, S.K. / Barratt, D. / Bodnarchuk, M.S. / Boyd, S. / Braybrooke, E. / Breed, J. / Cassar, D.J. / Cosulich, S. / Davies, M. / Davies, N.L. / Deng, C. / Eatherton, A. / ...Authors: Kettle, J.G. / Bagal, S.K. / Barratt, D. / Bodnarchuk, M.S. / Boyd, S. / Braybrooke, E. / Breed, J. / Cassar, D.J. / Cosulich, S. / Davies, M. / Davies, N.L. / Deng, C. / Eatherton, A. / Evans, L. / Feron, L.J. / Fillery, S. / Gleave, E.S. / Goldberg, F.W. / Cortes Gonzalez, M.A. / Guerot, C. / Haider, A. / Harlfinger, S. / Howells, R. / Jackson, A. / Johnstrom, P. / Kemmitt, P.D. / Koers, A. / Kondrashov, M. / Lamont, G.M. / Lamont, S. / Lewis, H.J. / Liu, L. / Mylrea, M. / Nash, S. / Niedbala, M.J. / Peter, A. / Phillips, C. / Pike, K. / Raubo, P. / Robb, G.R. / Ross, S. / Sanders, M.G. / Schou, M. / Simpson, I. / Steward, O.
History
DepositionSep 29, 2022Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jul 12, 2023Provider: repository / Type: Initial release
Revision 2.0Jul 19, 2023Group: Advisory / Atomic model ...Advisory / Atomic model / Data collection / Database references / Derived calculations / Polymer sequence / Source and taxonomy / Structure summary
Category: atom_site / citation ...atom_site / citation / citation_author / entity / entity_name_com / entity_poly / entity_poly_seq / entity_src_gen / pdbx_nonpoly_scheme / pdbx_poly_seq_scheme / pdbx_unobs_or_zero_occ_atoms / pdbx_validate_torsion / struct_conf / struct_ref / struct_ref_seq / struct_ref_seq_dif
Item: _atom_site.B_iso_or_equiv / _atom_site.Cartn_x ..._atom_site.B_iso_or_equiv / _atom_site.Cartn_x / _atom_site.Cartn_y / _atom_site.Cartn_z / _atom_site.auth_comp_id / _atom_site.label_comp_id / _citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _entity.formula_weight / _entity.pdbx_description / _entity.pdbx_ec / _entity_poly.pdbx_seq_one_letter_code / _entity_poly.pdbx_seq_one_letter_code_can / _entity_poly_seq.mon_id / _entity_src_gen.pdbx_gene_src_gene / _pdbx_nonpoly_scheme.auth_seq_num / _pdbx_poly_seq_scheme.mon_id / _pdbx_poly_seq_scheme.pdb_mon_id / _struct_conf.beg_auth_comp_id / _struct_conf.beg_label_comp_id / _struct_ref.db_code / _struct_ref.pdbx_db_accession / _struct_ref.pdbx_seq_one_letter_code / _struct_ref_seq.db_align_end / _struct_ref_seq.pdbx_auth_seq_align_end / _struct_ref_seq.pdbx_db_accession / _struct_ref_seq.seq_align_end
Revision 2.1Jul 26, 2023Group: Data collection / Database references / Category: citation / citation_author / diffrn_source
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID / _diffrn_source.pdbx_synchrotron_site
Revision 2.2Feb 7, 2024Group: 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: GTPase KRas
hetero molecules


Theoretical massNumber of molelcules
Total (without water)20,1054
Polymers19,1951
Non-polymers9103
Water2,234124
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)94.360, 94.360, 122.470
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number155
Space group name H-MH32
Components on special symmetry positions
IDModelComponents
11A-306-

HOH

21A-421-

HOH

31A-422-

HOH

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Components

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


Mass: 19194.633 Da / Num. of mol.: 1
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, small monomeric GTPase
#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 / Guanosine 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-PUO / 1-[(4~{a}~{R})-8-(2-chloranyl-6-oxidanyl-phenyl)-7-fluoranyl-9-prop-1-ynyl-1,2,4,4~{a},5,11-hexahydropyrazino[2,1-c][1,4]benzoxazepin-3-yl]propan-1-one


Mass: 442.910 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C24H24ClFN2O3 / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 124 / 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: 2.75 Å3/Da / Density % sol: 55.23 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / Details: PEG 3350 LITHIUM SULFATE

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I04 / Wavelength: 0.97948 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jul 17, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97948 Å / Relative weight: 1
ReflectionResolution: 1.11→67.98 Å / Num. obs: 66898 / % possible obs: 85 % / Redundancy: 7.2 % / CC1/2: 0.997 / Rmerge(I) obs: 0.08 / Rrim(I) all: 0.09 / Net I/σ(I): 10
Reflection shellResolution: 1.11→1.17 Å / Mean I/σ(I) obs: 0.7 / Num. unique obs: 700 / CC1/2: 0.372

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Processing

Software
NameVersionClassification
Aimlessdata scaling
BUSTERrefinement
PDB_EXTRACT3.27data extraction
XDSdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1o83

1o83


Resolution: 1.11→67.98 Å / Cor.coef. Fo:Fc: 0.951 / Cor.coef. Fo:Fc free: 0.937 / SU B: 0.443 / SU ML: 0.022 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.042 / ESU R Free: 0.042 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2357 3482 4.9 %RANDOM
Rwork0.2236 ---
obs0.2243 66898 85.03 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 75.44 Å2 / Biso mean: 20.835 Å2 / Biso min: 10.29 Å2
Baniso -1Baniso -2Baniso -3
1--0 Å2-0 Å2-0 Å2
2---0 Å2-0 Å2
3---0 Å2
Refinement stepCycle: final / Resolution: 1.11→67.98 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1340 0 60 124 1524
Biso mean--19.15 30.01 -
Num. residues----168
LS refinement shellResolution: 1.11→1.138 Å / Rfactor Rfree error: 0
RfactorNum. reflection% reflection
Rfree0.287 51 -
Rwork0.312 1074 -
obs--18.46 %

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