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- PDB-6t5v: KRasG12C ligand complex -

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Basic information

Entry
Database: PDB / ID: 6t5v
TitleKRasG12C ligand complex
ComponentsGTPase KRas
KeywordsSIGNALING PROTEIN / GTPase
Function / homology
Function and homology information


forebrain astrocyte development / negative regulation of epithelial cell differentiation / regulation of synaptic transmission, GABAergic / type I pneumocyte differentiation / epithelial tube branching involved in lung morphogenesis / 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 / type I pneumocyte differentiation / epithelial tube branching involved in lung morphogenesis / 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 / Activated NTRK2 signals through FRS2 and FRS3 / glial cell proliferation / 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 / Erythropoietin activates RAS / SHC-mediated cascade:FGFR1 / 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 / FRS-mediated FGFR2 signaling / FRS-mediated FGFR4 signaling / Signaling by FGFR3 in disease / homeostasis of number of cells within a tissue / 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 / Signaling by FGFR1 in disease / GRB2 events in ERBB2 signaling / CD209 (DC-SIGN) signaling / Ras activation upon Ca2+ influx through NMDA receptor / NCAM signaling for neurite out-growth / SHC1 events in ERBB2 signaling / Downstream signal transduction / Constitutive Signaling by Overexpressed ERBB2 / Insulin receptor signalling cascade / Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants / small monomeric GTPase / VEGFR2 mediated cell proliferation / FCERI mediated MAPK activation / Signaling by ERBB2 TMD/JMD mutants / RAF activation / Constitutive Signaling by EGFRvIII / regulation of long-term neuronal synaptic plasticity / Signaling by high-kinase activity BRAF mutants / Signaling by ERBB2 ECD mutants / MAP2K and MAPK activation / visual learning / Signaling by ERBB2 KD Mutants / Signaling by SCF-KIT / G protein activity / cytoplasmic side of plasma membrane / Regulation of RAS by GAPs / Signaling by CSF1 (M-CSF) in myeloid cells / RAS processing / Negative regulation of MAPK pathway / 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 / 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 / negative regulation of neuron apoptotic process / Ras protein signal transduction / mitochondrial outer membrane / 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 nucleotide triphosphate hydrolases ...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 nucleotide triphosphate hydrolases / Rossmann fold / P-loop containing nucleoside triphosphate hydrolase / 3-Layer(aba) Sandwich / Alpha Beta
Similarity search - Domain/homology
GUANOSINE-5'-DIPHOSPHATE / Chem-MKZ / GTPase KRas
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.31 Å
AuthorsPhillips, C.
CitationJournal: J.Med.Chem. / Year: 2020
Title: Structure-Based Design and Pharmacokinetic Optimization of Covalent Allosteric Inhibitors of the Mutant GTPase KRASG12C.
Authors: Kettle, J.G. / Bagal, S.K. / Bickerton, S. / Bodnarchuk, M.S. / Breed, J. / Carbajo, R.J. / Cassar, D.J. / Chakraborty, A. / Cosulich, S. / Cumming, I. / Davies, M. / Eatherton, A. / Evans, ...Authors: Kettle, J.G. / Bagal, S.K. / Bickerton, S. / Bodnarchuk, M.S. / Breed, J. / Carbajo, R.J. / Cassar, D.J. / Chakraborty, A. / Cosulich, S. / Cumming, I. / Davies, M. / Eatherton, A. / Evans, L. / Feron, L. / Fillery, S. / Gleave, E.S. / Goldberg, F.W. / Harlfinger, S. / Hanson, L. / Howard, M. / Howells, R. / Jackson, A. / Kemmitt, P. / Kingston, J.K. / Lamont, S. / Lewis, H.J. / Li, S. / Liu, L. / Ogg, D. / Phillips, C. / Polanski, R. / Robb, G. / Robinson, D. / Ross, S. / Smith, J.M. / Tonge, M. / Whiteley, R. / Yang, J. / Zhang, L. / Zhao, X.
History
DepositionOct 17, 2019Deposition site: PDBE / Processing site: PDBE
Revision 1.0Feb 19, 2020Provider: repository / Type: Initial release
Revision 1.1May 27, 2020Group: 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.name
Revision 1.2May 1, 2024Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / pdbx_struct_conn_angle / struct_conn
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_struct_conn_angle.ptnr1_auth_comp_id / _pdbx_struct_conn_angle.ptnr1_auth_seq_id / _pdbx_struct_conn_angle.ptnr1_label_asym_id / _pdbx_struct_conn_angle.ptnr1_label_atom_id / _pdbx_struct_conn_angle.ptnr1_label_comp_id / _pdbx_struct_conn_angle.ptnr3_auth_comp_id / _pdbx_struct_conn_angle.ptnr3_auth_seq_id / _pdbx_struct_conn_angle.ptnr3_label_asym_id / _pdbx_struct_conn_angle.ptnr3_label_atom_id / _pdbx_struct_conn_angle.ptnr3_label_comp_id / _pdbx_struct_conn_angle.value / _struct_conn.pdbx_dist_value / _struct_conn.ptnr2_auth_comp_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id / _struct_conn.ptnr2_label_atom_id / _struct_conn.ptnr2_label_comp_id

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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)20,1984
Polymers19,2961
Non-polymers9023
Water3,279182
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area880 Å2
ΔGint-19 kcal/mol
Surface area8220 Å2
MethodPISA
Unit cell
Length a, b, c (Å)40.421, 51.135, 90.186
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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Components

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


Mass: 19295.734 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
#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


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-MKZ / 1-[4-[6-chloranyl-7-(5-methyl-1~{H}-indazol-4-yl)quinazolin-4-yl]piperazin-1-yl]propan-1-one


Mass: 434.921 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C23H23ClN6O / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 182 / 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: 2.42 Å3/Da / Density % sol: 49.07 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / Details: 50mM HEPES 100mM NaCl 2mM MgSO4 / PH range: 7.2

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I03 / Wavelength: 0.97625 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Oct 9, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97625 Å / Relative weight: 1
ReflectionResolution: 1.31→45.09 Å / Num. obs: 45042 / % possible obs: 98.7 % / Redundancy: 5.6 % / Biso Wilson estimate: 14.5 Å2 / Rmerge(I) obs: 0.047 / Net I/σ(I): 20.9
Reflection shellResolution: 1.32→1.35 Å / Redundancy: 2.5 % / Rmerge(I) obs: 0.59 / Mean I/σ(I) obs: 2.4 / Num. unique obs: 2878 / % possible all: 88.3

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Processing

Software
NameVersionClassification
REFMAC5.8.0135refinement
PDB_EXTRACT3.25data extraction
XDSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: in house structure

Resolution: 1.31→45.09 Å / Cor.coef. Fo:Fc: 0.9606 / Cor.coef. Fo:Fc free: 0.9576 / SU R Cruickshank DPI: 0.047 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.05 / SU Rfree Blow DPI: 0.053 / SU Rfree Cruickshank DPI: 0.051
RfactorNum. reflection% reflectionSelection details
Rfree0.2052 2167 4.81 %RANDOM
Rwork0.1771 ---
obs0.1784 45042 98.51 %-
Displacement parametersBiso max: 128.52 Å2 / Biso mean: 20.31 Å2 / Biso min: 7.8 Å2
Baniso -1Baniso -2Baniso -3
1-1.3136 Å20 Å20 Å2
2--1.074 Å20 Å2
3----2.3876 Å2
Refine analyzeLuzzati coordinate error obs: 0.165 Å
Refinement stepCycle: final / Resolution: 1.31→45.09 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1344 0 82 182 1608
Biso mean--14.44 38.44 -
Num. residues----169
LS refinement shellResolution: 1.31→1.34 Å / Rfactor Rfree error: 0
RfactorNum. reflection% reflection
Rfree0.2823 142 4.93 %
Rwork0.28 2736 -
obs--86.66 %
Refinement TLS params.Method: refined / Origin x: -18.2141 Å / Origin y: 1.5105 Å / Origin z: -12.3391 Å
111213212223313233
T-0.0224 Å20.0081 Å20.0023 Å2--0.0403 Å2-0.0012 Å2---0.0484 Å2
L0.887 °20.2522 °20.0888 °2-1.1109 °20.0153 °2--1.5057 °2
S-0.033 Å °-0.0417 Å °0.0167 Å °-0.0702 Å °0.0257 Å °0.0494 Å °0.0398 Å °0.0316 Å °0.0073 Å °
Refinement TLS groupSelection details: { B|* }

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