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- PDB-4ldj: Crystal Structure of a GDP-bound G12C Oncogenic Mutant of Human G... -

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Basic information

Entry
Database: PDB / ID: 4ldj
TitleCrystal Structure of a GDP-bound G12C Oncogenic Mutant of Human GTPase KRas
ComponentsGTPase KRas
KeywordsHYDROLASE / Small GTPase / GDP bound / oncogenic mutation
Function / homology
Function and homology information


response to mineralocorticoid / GMP binding / forebrain astrocyte development / LRR domain binding / regulation of synaptic transmission, GABAergic / negative regulation of epithelial cell differentiation / response to isolation stress / response to gravity / epithelial tube branching involved in lung morphogenesis / type I pneumocyte differentiation ...response to mineralocorticoid / GMP binding / forebrain astrocyte development / LRR domain binding / regulation of synaptic transmission, GABAergic / negative regulation of epithelial cell differentiation / response to isolation stress / response to gravity / epithelial tube branching involved in lung morphogenesis / type I pneumocyte differentiation / Rac protein signal transduction / positive regulation of Rac protein signal transduction / Signaling by RAS GAP mutants / Signaling by RAS GTPase mutants / Activation of RAS in B cells / myoblast proliferation / skeletal muscle cell differentiation / RAS signaling downstream of NF1 loss-of-function variants / RUNX3 regulates p14-ARF / positive regulation of glial cell proliferation / SOS-mediated signalling / Activated NTRK3 signals through RAS / Activated NTRK2 signals through RAS / SHC1 events in ERBB4 signaling / cardiac muscle cell proliferation / Signalling to RAS / Activated NTRK2 signals through FRS2 and FRS3 / SHC-related events triggered by IGF1R / Estrogen-stimulated signaling through PRKCZ / glial cell proliferation / SHC-mediated cascade:FGFR3 / MET activates RAS signaling / SHC-mediated cascade:FGFR2 / 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:FGFR4 / Erythropoietin activates RAS / SHC-mediated cascade:FGFR1 / Signaling by FGFR4 in disease / FRS-mediated FGFR3 signaling / Signaling by CSF3 (G-CSF) / Signaling by FLT3 ITD and TKD mutants / FRS-mediated FGFR2 signaling / FRS-mediated FGFR4 signaling / p38MAPK events / FRS-mediated FGFR1 signaling / Signaling by FGFR3 in disease / protein-membrane adaptor activity / Tie2 Signaling / striated muscle cell differentiation / Signaling by FGFR2 in disease / GRB2 events in EGFR signaling / SHC1 events in EGFR signaling / Signaling by FLT3 fusion proteins / FLT3 Signaling / Signaling by FGFR1 in disease / EGFR Transactivation by Gastrin / NCAM signaling for neurite out-growth / homeostasis of number of cells within a tissue / CD209 (DC-SIGN) signaling / GRB2 events in ERBB2 signaling / Downstream signal transduction / Insulin receptor signalling cascade / SHC1 events in ERBB2 signaling / Ras activation upon Ca2+ influx through NMDA receptor / response to glucocorticoid / Constitutive Signaling by Overexpressed ERBB2 / Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants / VEGFR2 mediated cell proliferation / small monomeric GTPase / FCERI mediated MAPK activation / liver development / Signaling by ERBB2 TMD/JMD mutants / female pregnancy / RAF activation / Signaling by SCF-KIT / Signaling by high-kinase activity BRAF mutants / Constitutive Signaling by EGFRvIII / regulation of long-term neuronal synaptic plasticity / MAP2K and MAPK activation / Signaling by ERBB2 ECD mutants / Signaling by ERBB2 KD Mutants / visual learning / cytoplasmic side of plasma membrane / cytokine-mediated signaling pathway / 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 / Signaling by BRAF and RAF1 fusions / positive regulation of cellular senescence / DAP12 signaling / MAPK cascade / Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants
Similarity search - Function
Small GTPase, Ras-type / Small GTPase Ras domain 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 domain 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 / GTPase KRas
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.15 Å
AuthorsHunter, J.C. / Gurbani, D. / Chen, Z. / Westover, K.D.
CitationJournal: Proc.Natl.Acad.Sci.USA / Year: 2014
Title: In situ selectivity profiling and crystal structure of SML-8-73-1, an active site inhibitor of oncogenic K-Ras G12C.
Authors: Hunter, J.C. / Gurbani, D. / Ficarro, S.B. / Carrasco, M.A. / Lim, S.M. / Choi, H.G. / Xie, T. / Marto, J.A. / Chen, Z. / Gray, N.S. / Westover, K.D.
History
DepositionJun 24, 2013Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 4, 2014Provider: repository / Type: Initial release
Revision 1.1Jul 9, 2014Group: Database references
Revision 1.2Nov 15, 2017Group: Refinement description / Category: software
Revision 1.3Sep 20, 2023Group: 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 / struct_ref_seq_dif / struct_site
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.ptnr1_label_seq_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.ptnr3_label_seq_id / _pdbx_struct_conn_angle.value / _struct_conn.pdbx_dist_value / _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_seq_id / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_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)19,8423
Polymers19,3751
Non-polymers4682
Water4,504250
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)39.071, 40.724, 91.431
Angle α, β, γ (deg.)90.00, 90.00, 90.00
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 / GTPase KRas / N-terminally processed


Mass: 19374.902 Da / Num. of mol.: 1 / Fragment: UNP residues 1-169
Source method: isolated from a genetically manipulated source
Details: codon optimized for expression in E. coli / Source: (gene. exp.) Homo sapiens (human) / Gene: KRAS, KRAS2, RASK2 / Plasmid: pJexpress401 / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3) / References: UniProt: P01116
#2: 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
#3: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Mg
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 250 / Source method: isolated from a natural source / Formula: H2O
Sequence detailsTHE SEQUENCE MATCHES UNIPROT ENTRY P01116, ISOFORM 2B WITH IDENTIFIER P01116-2

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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: 1.88 Å3/Da / Density % sol: 34.47 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 8.5
Details: 0.2M Sodium Acetate pH4.5, 0.1M Tris pH 8.5, 28% PEG 3350, Vapor Diffusion, Hanging Drop, temperature 293K, VAPOR DIFFUSION, HANGING DROP

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 19-ID / Wavelength: 0.97918 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Jan 1, 2013
RadiationMonochromator: Rosenbaum-Rock high-resolution double-crystal monochromator
Protocol: SINGLE WAVELENGTH / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97918 Å / Relative weight: 1
ReflectionResolution: 1.15→50 Å / Num. all: 52856 / Num. obs: 52661 / % possible obs: 99.6 % / Observed criterion σ(I): 2 / Redundancy: 7 % / Biso Wilson estimate: 7.5 Å2 / Rmerge(I) obs: 0.075 / Χ2: 0.852 / Net I/σ(I): 9.6
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. unique allRsym valueΧ2% possible all
1.15-1.1730.3172.4824580.3170.54994.8
1.17-1.193.90.3093.1725760.3090.56198.6
1.19-1.215.10.2994.1725580.2990.578100
1.21-1.246.40.2725.4426290.2720.606100
1.24-1.277.40.246.9126230.240.615100
1.27-1.37.50.2127.6826010.2120.61100
1.3-1.337.60.199.126150.190.646100
1.33-1.367.60.16610.1426030.1660.638100
1.36-1.47.60.1511.726300.150.657100
1.4-1.457.60.12714.626320.1270.717100
1.45-1.57.60.11118.0526000.1110.825100
1.5-1.567.70.09821.1426330.0980.924100
1.56-1.637.70.09224.9526540.0921.026100
1.63-1.727.70.08426.4826070.0841.047100
1.72-1.837.70.0829.9326440.081.155100
1.83-1.977.60.08126.6126620.0811.065100
1.97-2.167.60.08326.0826690.0831.131100
2.16-2.487.50.07526.7326800.0751.049100
2.48-3.127.30.05733.5927260.0571.038100
3.12-507.30.06330.0728610.0631.02999.2

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassificationNB
DENZOdata reduction
SCALEPACKdata scaling
PHASER2.5.3phasing
PHENIX1.8.2_1309refinement
PDB_EXTRACT3.11data extraction
HKL-3000data collection
HKL-2000data reduction
HKL-2000data scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 4EPV

4epv


Resolution: 1.15→20.696 Å / Occupancy max: 1 / Occupancy min: 1 / SU ML: 0.08 / σ(F): 1.36 / Phase error: 13.43 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.1622 1977 3.76 %Random 5%
Rwork0.1318 ---
obs0.1329 52591 99.25 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 44.69 Å2 / Biso mean: 12.8817 Å2 / Biso min: 6.01 Å2
Refinement stepCycle: LAST / Resolution: 1.15→20.696 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1357 0 29 250 1636
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0151408
X-RAY DIFFRACTIONf_angle_d1.6741905
X-RAY DIFFRACTIONf_chiral_restr0.111212
X-RAY DIFFRACTIONf_plane_restr0.009244
X-RAY DIFFRACTIONf_dihedral_angle_d14.811534
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 14

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection allNum. reflection obs% reflection obs (%)
1.15-1.17640.21151100.155132453355324590
1.1764-1.20820.18021570.1341355237093552100
1.2082-1.24370.16431290.1201358337123583100
1.2437-1.28390.14641600.1148360637663606100
1.2839-1.32980.1551290.1097357937083579100
1.3298-1.3830.14131430.1116361837613618100
1.383-1.44590.15541400.1103363137713631100
1.4459-1.52210.14231450.1061359837433598100
1.5221-1.61750.13721430.1114363237753632100
1.6175-1.74230.15791330.1201363337663633100
1.7423-1.91750.15321420.1316366338053663100
1.9175-2.19470.15541430.1293368038233680100
2.1947-2.76410.1741460.1508372138673721100
2.7641-20.69950.17321570.1439387340303873100

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