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- PDB-7o70: KRasG12C ligand complex -

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Basic information

Entry
Database: PDB / ID: 7o70
TitleKRasG12C ligand complex
ComponentsGTPase KRas
KeywordsSIGNALING PROTEIN / Inhibitor
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 / SHC-related events triggered by IGF1R / glial cell proliferation / Activated NTRK2 signals through FRS2 and FRS3 / Estrogen-stimulated signaling through PRKCZ / SHC-mediated cascade:FGFR3 / MET activates RAS signaling / Signaling by PDGFRA transmembrane, juxtamembrane and kinase domain mutants / Signaling by PDGFRA extracellular domain mutants / SHC-mediated cascade:FGFR2 / PTK6 Regulates RHO GTPases, RAS GTPase and MAP kinases / 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) / Signaling by FLT3 ITD and TKD mutants / positive regulation of glial cell proliferation / homeostasis of number of cells within a tissue / FRS-mediated FGFR2 signaling / FRS-mediated FGFR4 signaling / Signaling by FGFR3 in disease / p38MAPK events / Tie2 Signaling / FRS-mediated FGFR1 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 / Signaling by FGFR1 in disease / 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 / Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants / G protein activity / VEGFR2 mediated cell proliferation / FCERI mediated MAPK activation / Signaling by ERBB2 TMD/JMD mutants / RAF activation / regulation of long-term neuronal synaptic plasticity / Signaling by high-kinase activity BRAF mutants / Constitutive Signaling by EGFRvIII / MAP2K and MAPK activation / visual learning / 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 / Signaling by moderate kinase activity BRAF mutants / Paradoxical activation of RAF signaling by kinase inactive BRAF / Signaling downstream of RAS mutants / GDP binding / 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 / 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-V4T / GTPase KRas
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.18 Å
AuthorsPhillips, C.
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 12, 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

Downloads & links

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)40,69510
Polymers38,7062
Non-polymers1,9898
Water6,738374
1
A: GTPase KRas
hetero molecules


Theoretical massNumber of molelcules
Total (without water)20,3475
Polymers19,3531
Non-polymers9944
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
D: GTPase KRas
hetero molecules


Theoretical massNumber of molelcules
Total (without water)20,3475
Polymers19,3531
Non-polymers9944
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)33.380, 70.460, 66.150
Angle α, β, γ (deg.)90.000, 90.260, 90.000
Int Tables number4
Space group name H-MP1211

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Components

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Protein , 1 types, 2 molecules AD

#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

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Non-polymers , 5 types, 382 molecules

#2: Chemical ChemComp-V4T / 1-[(4R,7S)-12-chloro-14-fluoro-13-(2-fluoro-6-hydroxyphenyl)-4-methyl-10-oxa-2,5,16,18-tetrazatetracyclo[9.7.1.0^(2,7).0^(15,19)]nonadeca-1(18),11,13,15(19),16-pentaen-5-en-1-one-yl]prop-2 / 146250992


Mass: 486.898 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C24H21ClF2N4O3 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Mg
#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-CA / CALCIUM ION


Mass: 40.078 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Ca
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 374 / 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: 2.01 Å3/Da / Density % sol: 38.8 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / Details: 50mM HEPES pH 7.4, 100mM NaCl, 2mM MgSO4

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I04 / Wavelength: 1 Å
DetectorType: DECTRIS EIGER R 4M / Detector: PIXEL / Date: Jun 10, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.18→33.08 Å / Num. obs: 75362 / % possible obs: 75.8 % / Redundancy: 3 % / CC1/2: 0.998 / Rmerge(I) obs: 0.045 / Rpim(I) all: 0.029 / Rrim(I) all: 0.054 / Net I/σ(I): 10.9 / Num. measured all: 226688 / Scaling rejects: 194
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsCC1/2Rpim(I) allRrim(I) all% possible all
1.18-1.221.30.2685970.8070.2650.378
5.16-33.083.50.03411820.9970.0220.0494.6

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Processing

Software
NameVersionClassification
Aimless0.7.4data scaling
REFMAC5.8.0238refinement
PDB_EXTRACT3.27data extraction
autoPROCdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: NA

Resolution: 1.18→17.03 Å / Cor.coef. Fo:Fc: 0.953 / Cor.coef. Fo:Fc free: 0.94 / SU B: 0.591 / SU ML: 0.028 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.069 / ESU R Free: 0.072 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2566 3816 5.1 %RANDOM
Rwork0.2256 ---
obs0.2271 71493 75.73 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 72.05 Å2 / Biso mean: 15.015 Å2 / Biso min: 5.93 Å2
Baniso -1Baniso -2Baniso -3
1-0 Å20 Å20 Å2
2---0 Å2-0 Å2
3---0 Å2
Refinement stepCycle: final / Resolution: 1.18→17.03 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2680 0 128 374 3182
Biso mean--14.51 30.51 -
Num. residues----336
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0160.0132860
X-RAY DIFFRACTIONr_bond_other_d0.0010.0172598
X-RAY DIFFRACTIONr_angle_refined_deg2.0451.6923880
X-RAY DIFFRACTIONr_angle_other_deg1.5581.6216024
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.825334
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.10922.564156
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.81315498
X-RAY DIFFRACTIONr_dihedral_angle_4_deg11.9561520
X-RAY DIFFRACTIONr_chiral_restr0.1080.2372
X-RAY DIFFRACTIONr_gen_planes_refined0.0120.023360
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02588
LS refinement shellResolution: 1.184→1.215 Å / Rfactor Rfree error: 0 /
RfactorNum. reflection
Rfree0.206 34
Rwork-513

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