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- PDB-6cu6: Crystal structure of GMPPNP-bound G12R mutant of human KRAS4b -

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Basic information

Entry
Database: PDB / ID: 6cu6
TitleCrystal structure of GMPPNP-bound G12R mutant of human KRAS4b
ComponentsGTPase KRas
KeywordsONCOPROTEIN / KRAS / RAS / G12R / G12 / KRAS4b / K-RAS
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 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 / P-loop containing nucleoside triphosphate hydrolase / Rossmann fold / 3-Layer(aba) Sandwich / Alpha Beta
Similarity search - Domain/homology
PHOSPHOAMINOPHOSPHONIC ACID-GUANYLATE ESTER / GTPase KRas
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.5 Å
AuthorsTran, T.H. / Simanshu, D.K.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Cancer Institute (NIH/NCI)HHSN261200800001E United States
CitationJournal: Cancer Discov / Year: 2020
Title: Atypical KRASG12RMutant Is Impaired in PI3K Signaling and Macropinocytosis in Pancreatic Cancer.
Authors: Hobbs, G.A. / Baker, N.M. / Miermont, A.M. / Thurman, R.D. / Pierobon, M. / Tran, T.H. / Anderson, A.O. / Waters, A.M. / Diehl, J.N. / Papke, B. / Hodge, R.G. / Klomp, J.E. / Goodwin, C.M. / ...Authors: Hobbs, G.A. / Baker, N.M. / Miermont, A.M. / Thurman, R.D. / Pierobon, M. / Tran, T.H. / Anderson, A.O. / Waters, A.M. / Diehl, J.N. / Papke, B. / Hodge, R.G. / Klomp, J.E. / Goodwin, C.M. / DeLiberty, J.M. / Wang, J. / Ng, R.W.S. / Gautam, P. / Bryant, K.L. / Esposito, D. / Campbell, S.L. / Petricoin 3rd, E.F. / Simanshu, D.K. / Aguirre, A.J. / Wolpin, B.M. / Wennerberg, K. / Rudloff, U. / Cox, A.D. / Der, C.J.
History
DepositionMar 23, 2018Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 25, 2019Provider: repository / Type: Initial release
Revision 1.1Nov 13, 2019Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Dec 4, 2019Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.3Jan 22, 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.year / _citation_author.identifier_ORCID / _citation_author.name
Revision 1.4Mar 13, 2024Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / 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.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
Revision 1.5Apr 3, 2024Group: Refinement description / Category: 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
B: GTPase KRas
C: GTPase KRas
hetero molecules


Theoretical massNumber of molelcules
Total (without water)60,01810
Polymers58,2873
Non-polymers1,7327
Water4,179232
1
A: GTPase KRas
hetero molecules


Theoretical massNumber of molelcules
Total (without water)19,9753
Polymers19,4291
Non-polymers5472
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: GTPase KRas
hetero molecules


Theoretical massNumber of molelcules
Total (without water)20,0684
Polymers19,4291
Non-polymers6393
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
C: GTPase KRas
hetero molecules


Theoretical massNumber of molelcules
Total (without water)19,9753
Polymers19,4291
Non-polymers5472
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)67.790, 83.295, 86.040
Angle α, β, γ (deg.)90.000, 110.100, 90.000
Int Tables number5
Space group name H-MC121
Components on special symmetry positions
IDModelComponents
11B-583-

HOH

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Components

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


Mass: 19428.953 Da / Num. of mol.: 3 / Mutation: G12R
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.: 3 / Source method: obtained synthetically / Formula: Mg / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-GNP / PHOSPHOAMINOPHOSPHONIC ACID-GUANYLATE ESTER


Mass: 522.196 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C10H17N6O13P3 / Feature type: SUBJECT OF INVESTIGATION
Comment: GppNHp, GMPPNP, energy-carrying molecule analogue*YM
#4: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 232 / Source method: isolated from a natural source / Formula: H2O

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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: 1.97 Å3/Da / Density % sol: 37.56 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 7.5
Details: 2.1 M Sodium Malonate pH 7.5, 40 mM Dimethyloctylphosphine oxide

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 24-ID-E / Wavelength: 0.97918 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Aug 3, 2017
Details: Cryogenically-cooled single crystal Si(220) side bounce monochromator
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97918 Å / Relative weight: 1
ReflectionResolution: 1.5→50.58 Å / Num. obs: 70088 / % possible obs: 95.5 % / Redundancy: 2.325 % / Biso Wilson estimate: 26.11 Å2 / CC1/2: 0.997 / Rmerge(I) obs: 0.048 / Rrim(I) all: 0.061 / Χ2: 1.18 / Net I/σ(I): 8.93 / Num. measured all: 317030
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. unique obsCC1/2Rrim(I) all% possible all
1.5-1.592.280.8730.91212550.51.12992
1.59-1.72.3120.5021.75204950.7640.64694.5
1.7-1.832.240.2773.35193520.9180.35895.8
1.83-2.012.4470.1556.68181110.9690.19797.5
2.01-2.242.3870.08711.3164640.9870.1197.6
2.24-2.592.2450.05715.09141940.9930.07396
2.59-3.172.3950.04419.85122070.9950.05797.1
3.17-4.472.3020.03923.0192640.9950.0595.5
4.47-50.582.340.03624.0550430.9950.04694.6

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Processing

Software
NameVersionClassification
PHENIXrefinement
XDSdata reduction
XDSdata scaling
PHASERphasing
PDB_EXTRACT3.24data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: GMPPNP-bound KRAS4B

Resolution: 1.5→50.58 Å / SU ML: 0.21 / Cross valid method: THROUGHOUT / σ(F): 1.37 / Phase error: 29.1
RfactorNum. reflection% reflection
Rfree0.2296 1854 2.65 %
Rwork0.2024 --
obs0.2031 70088 97.64 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso max: 115.27 Å2 / Biso mean: 40.7487 Å2 / Biso min: 18 Å2
Refinement stepCycle: final / Resolution: 1.5→50.58 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3847 0 105 232 4184
Biso mean--33.54 41.7 -
Num. residues----486
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 13

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
1.5-1.54060.371440.355089523394
1.5406-1.58590.34511350.31265101523696
1.5859-1.63710.32761380.28435107524596
1.6371-1.69560.32191390.27695183532297
1.6956-1.76350.30531450.26655233537898
1.7635-1.84380.27181390.24895268540798
1.8438-1.9410.31450.24425294543998
1.941-2.06260.23781500.22375310546099
2.0626-2.22180.21931410.21825311545299
2.2218-2.44540.26911430.21295309545299
2.4454-2.79930.22411400.21775295543599
2.7993-3.52660.20891470.195356550399
3.5266-50.6090.19691480.16455378552698

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