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- PDB-6t5u: KRasG12C ligand complex -

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Basic information

Entry
Database: PDB / ID: 6t5u
TitleKRasG12C ligand complex
ComponentsV-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog, isoform CRA_b
KeywordsSIGNALING PROTEIN / GTPase
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 / Signaling by RAS GAP mutants ...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 / 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 / protein-membrane adaptor activity / Signaling by FGFR4 in disease / SHC-mediated cascade:FGFR1 / Erythropoietin activates RAS / homeostasis of number of cells within a tissue / 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 / GRB2 events in EGFR signaling / striated muscle cell differentiation / SHC1 events in EGFR signaling / EGFR Transactivation by Gastrin / Signaling by FLT3 fusion proteins / Ras activation upon Ca2+ influx through NMDA receptor / FLT3 Signaling / 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 / Insulin receptor signalling cascade / Constitutive Signaling by Overexpressed ERBB2 / small monomeric GTPase / G protein activity / Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants / VEGFR2 mediated cell proliferation / FCERI mediated MAPK activation / regulation of long-term neuronal synaptic plasticity / Signaling by ERBB2 TMD/JMD mutants / 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 / negative regulation of neuron apoptotic process / mitochondrial outer membrane / positive regulation of protein phosphorylation / Golgi membrane
Similarity search - Function
small GTPase Rab1 family profile. / small GTPase Rho family profile. / 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 GTPase Rab1 family profile. / small GTPase Rho family profile. / 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 / P-loop containing nucleoside triphosphate hydrolase / Rossmann fold / 3-Layer(aba) Sandwich / Alpha Beta
Similarity search - Domain/homology
GUANOSINE-5'-DIPHOSPHATE / Chem-MKW / V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog, isoform CRA_b / GTPase KRas isoform X2 / GTPase KRas
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.72 Å
AuthorsPhillips, C.
Citation
Journal: 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.
#1: Journal: To Be Published
Title: KRasG12C ligand complex
Authors: Phillips, C.
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 2.0Feb 10, 2021Group: Advisory / Atomic model ...Advisory / Atomic model / Data collection / Database references / Derived calculations / Other / Polymer sequence / Source and taxonomy / Structure summary
Category: atom_site / cell ...atom_site / cell / entity / entity_poly / entity_poly_seq / entity_src_gen / pdbx_entity_nonpoly / pdbx_nonpoly_scheme / pdbx_poly_seq_scheme / pdbx_struct_conn_angle / pdbx_unobs_or_zero_occ_residues / struct_asym / struct_conn / 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.label_entity_id / _cell.Z_PDB / _pdbx_entity_nonpoly.entity_id / _pdbx_nonpoly_scheme.auth_seq_num / _pdbx_nonpoly_scheme.entity_id / _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_asym.entity_id / _struct_conn.conn_type_id / _struct_conn.id / _struct_conn.pdbx_dist_value / _struct_conn.pdbx_leaving_atom_flag / _struct_conn.ptnr1_auth_asym_id / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr2_auth_asym_id / _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 / _struct_ref_seq.db_align_end / _struct_ref_seq.pdbx_auth_seq_align_end / _struct_ref_seq.pdbx_db_accession / _struct_ref_seq.ref_id / _struct_ref_seq.seq_align_end

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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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)40,0488
Polymers38,1892
Non-polymers1,8596
Water3,027168
1
A: V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog, isoform CRA_b
hetero molecules


Theoretical massNumber of molelcules
Total (without water)20,0244
Polymers19,0941
Non-polymers9293
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)20,0244
Polymers19,0941
Non-polymers9293
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)33.597, 41.084, 65.192
Angle α, β, γ (deg.)78.470, 85.590, 68.140
Int Tables number1
Space group name H-MP1

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Components

#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 phage EcSzw-2 (virus) / References: UniProt: A0A024RAV5, UniProt: A0A1S2ZE25*PLUS
#2: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Mg / References: UniProt: P01116*PLUS
#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-MKW / 1-[(7R)-16-chloro-15-(5-methyl-1H-indazol-4-yl)-9-oxa-2,5,12-triazatetracyclo[8.8.0.02,7.013,18]octadeca-1(10),11,13,15,17-pentaen-5-yl]prop-2-en-1-one


Mass: 461.943 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C25H24ClN5O2 / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 168 / 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 / pH: 7.4 / 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: I04 / Wavelength: 0.98 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Jun 5, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.98 Å / Relative weight: 1
ReflectionResolution: 1.72→31.94 Å / Num. obs: 28875 / % possible obs: 90 % / Redundancy: 1.8 % / Rmerge(I) obs: 0.005 / Net I/σ(I): 8.9
Reflection shellResolution: 1.72→1.765 Å / Rmerge(I) obs: 0.72 / Num. unique obs: 2168

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Processing

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

Resolution: 1.72→31.94 Å / Cor.coef. Fo:Fc: 0.951 / Cor.coef. Fo:Fc free: 0.931 / SU B: 3.459 / SU ML: 0.113 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.18 / ESU R Free: 0.169 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2908 1460 4.8 %RANDOM
Rwork0.2373 ---
obs0.2399 28875 90.04 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 108.31 Å2 / Biso mean: 34.044 Å2 / Biso min: 9.96 Å2
Baniso -1Baniso -2Baniso -3
1-0.04 Å20.02 Å2-0.01 Å2
2---0.05 Å20.02 Å2
3---0.04 Å2
Refinement stepCycle: final / Resolution: 1.72→31.94 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2671 0 124 168 2963
Biso mean--30.28 47.04 -
Num. residues----335
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0190.0192876
X-RAY DIFFRACTIONr_bond_other_d0.0020.022670
X-RAY DIFFRACTIONr_angle_refined_deg2.1261.9753907
X-RAY DIFFRACTIONr_angle_other_deg1.1113.0016143
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.225337
X-RAY DIFFRACTIONr_dihedral_angle_2_deg43.32924.348138
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.87915496
X-RAY DIFFRACTIONr_dihedral_angle_4_deg16.3061520
X-RAY DIFFRACTIONr_chiral_restr0.120.2425
X-RAY DIFFRACTIONr_gen_planes_refined0.010.023198
X-RAY DIFFRACTIONr_gen_planes_other0.0020.02650
LS refinement shellResolution: 1.72→1.765 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.474 123 -
Rwork0.41 2168 -
all-2291 -
obs--90.16 %

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