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- PDB-8b6i: KRasG12C ligand complex -

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Basic information

Entry
Database: PDB / ID: 8b6i
TitleKRasG12C ligand complex
ComponentsGTPase KRas
KeywordsSIGNALING PROTEIN / INHIBITOR COMPLEX
Function / homology
Function and homology information


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 / Signaling by RAS GAP mutants / Signaling by RAS GTPase mutants ...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 / 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 / homeostasis of number of cells within a tissue / protein-membrane adaptor activity / positive regulation of glial cell proliferation / FRS-mediated FGFR3 signaling / Signaling by CSF3 (G-CSF) / Signaling by FLT3 ITD and TKD mutants / FRS-mediated FGFR2 signaling / FRS-mediated FGFR4 signaling / Signaling by FGFR3 in disease / p38MAPK events / FRS-mediated FGFR1 signaling / 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 / Ras activation upon Ca2+ influx through NMDA receptor / GRB2 events in ERBB2 signaling / Signaling by FGFR1 in disease / 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 / GDP binding / Signaling by RAF1 mutants / 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 / Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants / DAP12 signaling / Ca2+ pathway / gene expression / actin cytoskeleton organization / RAF/MAP kinase cascade / neuron apoptotic process / Ras protein signal transduction / mitochondrial outer membrane / negative regulation of neuron apoptotic process / 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-PQI / GTPase KRas
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.7 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 27, 2022Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jul 12, 2023Provider: repository / Type: Initial release
Revision 1.1Jul 19, 2023Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._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
Revision 1.2Jul 26, 2023Group: 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 1.3Feb 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

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Assembly

Deposited unit
A: GTPase KRas
B: GTPase KRas
hetero molecules


Theoretical massNumber of molelcules
Total (without water)40,53910
Polymers38,7062
Non-polymers1,8338
Water2,540141
1
A: GTPase KRas
hetero molecules


Theoretical massNumber of molelcules
Total (without water)20,2705
Polymers19,3531
Non-polymers9174
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: GTPase KRas
hetero molecules


Theoretical massNumber of molelcules
Total (without water)20,2705
Polymers19,3531
Non-polymers9174
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)33.650, 39.190, 65.590
Angle α, β, γ (deg.)95.630, 95.180, 103.250
Int Tables number1
Space group name H-MP1

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Components

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


Mass: 19352.785 Da / Num. of mol.: 2
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
#2: Chemical
ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 4 / 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-PQI / 1-[(4~{a}~{S})-7-chloranyl-8-(5-methyl-2~{H}-indazol-4-yl)-1,2,4,4~{a},5,11-hexahydropyrazino[2,1-c][1,4]benzoxazepin-3-yl]propan-1-one


Mass: 424.923 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C23H25ClN4O2 / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 141 / 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: 2.15 Å3/Da / Density % sol: 42.79 %
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: SOLEIL / Beamline: PROXIMA 2 / Wavelength: 0.98005 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Apr 10, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.98005 Å / Relative weight: 1
ReflectionResolution: 1.7→37.86 Å / Num. obs: 32694 / % possible obs: 91.8 % / Redundancy: 1.8 % / CC1/2: 0.998 / Rmerge(I) obs: 0.037 / Rpim(I) all: 0.037 / Rrim(I) all: 0.052 / Net I/σ(I): 11.4 / Num. measured all: 60290
Reflection shellResolution: 1.7→1.74 Å / Redundancy: 1.9 % / Rmerge(I) obs: 0.265 / Mean I/σ(I) obs: 2.2 / Num. measured all: 4003 / Num. unique obs: 2162 / CC1/2: 0.924 / Rpim(I) all: 0.265 / Rrim(I) all: 0.375 / Net I/σ(I) obs: 2.2 / % possible all: 82.1

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Processing

Software
NameVersionClassification
Aimless0.5.31data scaling
BUSTERrefinement
PDB_EXTRACT3.27data extraction
XDSdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 7o83

7o83


Resolution: 1.7→21.73 Å / Cor.coef. Fo:Fc: 0.952 / Cor.coef. Fo:Fc free: 0.927 / SU B: 2.63 / SU ML: 0.086 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.142 / ESU R Free: 0.135 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2413 1633 5 %RANDOM
Rwork0.196 ---
obs0.1983 31018 92.07 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 74.42 Å2 / Biso mean: 21.228 Å2 / Biso min: 7.2 Å2
Baniso -1Baniso -2Baniso -3
1--0.46 Å20.49 Å2-0.9 Å2
2--0.84 Å20.58 Å2
3----0.64 Å2
Refinement stepCycle: final / Resolution: 1.7→21.73 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2680 0 120 141 2941
Biso mean--17.82 25.29 -
Num. residues----336
LS refinement shellResolution: 1.7→1.744 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.436 112 -
Rwork0.387 2121 -
all-2233 -
obs--86.25 %

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