+Open data
-Basic information
Entry | Database: EMDB / ID: EMD-22857 | |||||||||
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Title | Structure of a ternary KRas(G13D)-SOS complex | |||||||||
Map data | ||||||||||
Sample |
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Keywords | Ras / Sos / GTPase / HYDROLASE-SIGNALING PROTEIN complex | |||||||||
Function / homology | Function and homology information midbrain morphogenesis / regulation of pro-B cell differentiation / vitellogenesis / pericardium morphogenesis / cardiac atrium morphogenesis / heart trabecula morphogenesis / regulation of T cell differentiation in thymus / GTPase complex / positive regulation of small GTPase mediated signal transduction / Interleukin-15 signaling ...midbrain morphogenesis / regulation of pro-B cell differentiation / vitellogenesis / pericardium morphogenesis / cardiac atrium morphogenesis / heart trabecula morphogenesis / regulation of T cell differentiation in thymus / GTPase complex / positive regulation of small GTPase mediated signal transduction / Interleukin-15 signaling / Activation of RAC1 / blood vessel morphogenesis / forebrain astrocyte development / positive regulation of epidermal growth factor receptor signaling pathway / negative regulation of epithelial cell differentiation / regulation of synaptic transmission, GABAergic / epithelial tube branching involved in lung morphogenesis / Regulation of KIT signaling / epidermal growth factor receptor binding / type I pneumocyte differentiation / leukocyte migration / regulation of T cell proliferation / NRAGE signals death through JNK / roof of mouth development / Rac protein signal transduction / eyelid development in camera-type eye / 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 / Fc-epsilon receptor signaling pathway / GRB2:SOS provides linkage to MAPK signaling for Integrins / B cell homeostasis / neurotrophin TRK receptor signaling pathway / RAS signaling downstream of NF1 loss-of-function variants / RUNX3 regulates p14-ARF / SOS-mediated signalling / RET signaling / Activated NTRK3 signals through RAS / Activated NTRK2 signals through RAS / hair follicle development / SHC1 events in ERBB4 signaling / Signalling to RAS / fibroblast growth factor receptor signaling pathway / SHC-related events triggered by IGF1R / glial cell proliferation / Activated NTRK2 signals through FRS2 and FRS3 / Role of LAT2/NTAL/LAB on calcium mobilization / Interleukin receptor SHC signaling / Signal attenuation / 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 / Schwann cell development / 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 / Signaling by FGFR3 in disease / FRS-mediated FGFR4 signaling / p38MAPK events / Tie2 Signaling / FRS-mediated FGFR1 signaling / striated muscle cell differentiation / Signaling by FGFR2 in disease / GRB2 events in EGFR signaling / SHC1 events in EGFR signaling / RAC1 GTPase cycle / EGFR Transactivation by Gastrin / Signaling by FLT3 fusion proteins / FLT3 Signaling / Ras activation upon Ca2+ influx through NMDA receptor / myelination / Signaling by FGFR1 in disease / GRB2 events in ERBB2 signaling / CD209 (DC-SIGN) signaling / NCAM signaling for neurite out-growth / SHC1 events in ERBB2 signaling / Downstream signal transduction / Constitutive Signaling by Overexpressed ERBB2 / FCERI mediated Ca+2 mobilization / Insulin receptor signalling cascade / GTPase activator activity / insulin-like growth factor receptor signaling pathway / small monomeric GTPase / guanyl-nucleotide exchange factor activity / Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants / G protein activity Similarity search - Function | |||||||||
Biological species | Homo sapiens (human) | |||||||||
Method | single particle reconstruction / cryo EM / Resolution: 3.47 Å | |||||||||
Authors | Liu C / Moghadamchargari Z | |||||||||
Funding support | United States, 1 items
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Citation | Journal: Proc Natl Acad Sci U S A / Year: 2021 Title: Molecular assemblies of the catalytic domain of SOS with KRas and oncogenic mutants. Authors: Zahra Moghadamchargari / Mehdi Shirzadeh / Chang Liu / Samantha Schrecke / Charles Packianathan / David H Russell / Minglei Zhao / Arthur Laganowsky / Abstract: Ras is regulated by a specific guanine nucleotide exchange factor Son of Sevenless (SOS), which facilitates the exchange of inactive, GDP-bound Ras with GTP. The catalytic activity of SOS is also ...Ras is regulated by a specific guanine nucleotide exchange factor Son of Sevenless (SOS), which facilitates the exchange of inactive, GDP-bound Ras with GTP. The catalytic activity of SOS is also allosterically modulated by an active Ras (Ras-GTP). However, it remains poorly understood how oncogenic Ras mutants interact with SOS and modulate its activity. Here, native ion mobility-mass spectrometry is employed to monitor the assembly of the catalytic domain of SOS (SOS) with KRas and three cancer-associated mutants (G12C, G13D, and Q61H), leading to the discovery of different molecular assemblies and distinct conformers of SOS engaging KRas. We also find KRas exhibits high affinity for SOS and is a potent allosteric modulator of its activity. A structure of the KRas•SOS complex was determined using cryogenic electron microscopy providing insight into the enhanced affinity of the mutant protein. In addition, we find that KRas-GTP can allosterically increase the nucleotide exchange rate of KRas at the active site more than twofold compared to KRas-GTP. Furthermore, small-molecule Ras•SOS disruptors fail to dissociate KRas•SOS complexes, underscoring the need for more potent disruptors. Taken together, a better understanding of the interaction between oncogenic Ras mutants and SOS will provide avenues for improved therapeutic interventions. | |||||||||
History |
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-Structure visualization
Movie |
Movie viewer |
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Structure viewer | EM map: SurfViewMolmilJmol/JSmol |
Supplemental images |
-Downloads & links
-EMDB archive
Map data | emd_22857.map.gz | 20.6 MB | EMDB map data format | |
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Header (meta data) | emd-22857-v30.xml emd-22857.xml | 20.2 KB 20.2 KB | Display Display | EMDB header |
FSC (resolution estimation) | emd_22857_fsc.xml | 6.9 KB | Display | FSC data file |
Images | emd_22857.png | 129.7 KB | ||
Masks | emd_22857_msk_1.map | 27 MB | Mask map | |
Filedesc metadata | emd-22857.cif.gz | 6.2 KB | ||
Others | emd_22857_additional_1.map.gz emd_22857_half_map_1.map.gz emd_22857_half_map_2.map.gz | 25.2 MB 20.7 MB 20.7 MB | ||
Archive directory | http://ftp.pdbj.org/pub/emdb/structures/EMD-22857 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-22857 | HTTPS FTP |
-Validation report
Summary document | emd_22857_validation.pdf.gz | 699.1 KB | Display | EMDB validaton report |
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Full document | emd_22857_full_validation.pdf.gz | 698.7 KB | Display | |
Data in XML | emd_22857_validation.xml.gz | 12.4 KB | Display | |
Data in CIF | emd_22857_validation.cif.gz | 17.2 KB | Display | |
Arichive directory | https://ftp.pdbj.org/pub/emdb/validation_reports/EMD-22857 ftp://ftp.pdbj.org/pub/emdb/validation_reports/EMD-22857 | HTTPS FTP |
-Related structure data
Related structure data | 7kfzMC M: atomic model generated by this map C: citing same article (ref.) |
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Similar structure data | |
EM raw data | EMPIAR-10894 (Title: Single-particle cryoEM data of a ternary KRas(G13D)-SOS complex Data size: 3.7 TB Data #1: Unaligned raw movie of SOS-KRas (G13D) complex [micrographs - multiframe]) |
-Links
EMDB pages | EMDB (EBI/PDBe) / EMDataResource |
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Related items in Molecule of the Month |
-Map
File | Download / File: emd_22857.map.gz / Format: CCP4 / Size: 27 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Voxel size | X=Y=Z: 1.065 Å | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Details | EMDB XML:
CCP4 map header:
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-Supplemental data
-Mask #1
File | emd_22857_msk_1.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
-Additional map: #1
File | emd_22857_additional_1.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
-Half map: #1
File | emd_22857_half_map_1.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
-Half map: #2
File | emd_22857_half_map_2.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
-Sample components
-Entire : A ternary complex of KRas(G13D) and SOScat
Entire | Name: A ternary complex of KRas(G13D) and SOScat |
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Components |
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-Supramolecule #1: A ternary complex of KRas(G13D) and SOScat
Supramolecule | Name: A ternary complex of KRas(G13D) and SOScat / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#2 |
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Source (natural) | Organism: Homo sapiens (human) |
Molecular weight | Theoretical: 96.7 KDa |
-Macromolecule #1: GTPase KRas
Macromolecule | Name: GTPase KRas / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO / EC number: small monomeric GTPase |
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Source (natural) | Organism: Homo sapiens (human) |
Molecular weight | Theoretical: 19.386848 KDa |
Recombinant expression | Organism: Escherichia coli (E. coli) |
Sequence | String: GMTEYKLVVV GAGDVGKSAL TIQLIQNHFV DEYDPTIEDS YRKQVVIDGE TCLLDILDTA GQEEYSAMRD QYMRTGEGFL CVFAINNTK SFEDIHHYRE QIKRVKDSED VPMVLVGNKC DLPSRTVDTK QAQDLARSYG IPFIETSAKT RQGVDDAFYT L VREIRKHK EK UniProtKB: GTPase KRas |
-Macromolecule #2: Son of sevenless homolog 1
Macromolecule | Name: Son of sevenless homolog 1 / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: Homo sapiens (human) |
Molecular weight | Theoretical: 57.449691 KDa |
Recombinant expression | Organism: Escherichia coli (E. coli) |
Sequence | String: GAMGSEEQMR LPSADVYRFA EPDSEENIIF EENMQPKAGI PIIKAGTVIK LIERLTYHMY ADPNFVRTFL TTYRSFCKPQ ELLSLIIER FEIPEPEPTE ADRIAIENGD QPLSAELKRF RKEYIQPVQL RVLNVCRHWV EHHFYDFERD AYLLQRMEEF I GTVRGKAM ...String: GAMGSEEQMR LPSADVYRFA EPDSEENIIF EENMQPKAGI PIIKAGTVIK LIERLTYHMY ADPNFVRTFL TTYRSFCKPQ ELLSLIIER FEIPEPEPTE ADRIAIENGD QPLSAELKRF RKEYIQPVQL RVLNVCRHWV EHHFYDFERD AYLLQRMEEF I GTVRGKAM KKWVESITKI IQRKKIARDN GPGHNITFQS SPPTVEWHIS RPGHIETFDL LTLHPIEIAR QLTLLESDLY RA VQPSELV GSVWTKEDKE INSPNLLKMI RHTTNLTLWF EKCIVETENL EERVAVVSRI IEILQVFQEL NNFNGVLEVV SAM NSSPVY RLDHTFEQIP SRQKKILEEA HELSEDHYKK YLAKLRSINP PCVPFFGIYL TNILKTEEGN PEVLKRHGKE LINF SKRRK VAEITGEIQQ YQNQPYCLRV ESDIKRFFEN LNPMGNSMEK EFTDYLFNKS LEIEPRNPKP LPRFPKKYSY PLKSP GVRP SNPRPGT UniProtKB: Son of sevenless homolog 1 |
-Macromolecule #3: PHOSPHOAMINOPHOSPHONIC ACID-GUANYLATE ESTER
Macromolecule | Name: PHOSPHOAMINOPHOSPHONIC ACID-GUANYLATE ESTER / type: ligand / ID: 3 / Number of copies: 1 / Formula: GNP |
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Molecular weight | Theoretical: 522.196 Da |
Chemical component information | ChemComp-GNP: |
-Macromolecule #4: MAGNESIUM ION
Macromolecule | Name: MAGNESIUM ION / type: ligand / ID: 4 / Number of copies: 1 / Formula: MG |
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Molecular weight | Theoretical: 24.305 Da |
-Experimental details
-Structure determination
Method | cryo EM |
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Processing | single particle reconstruction |
Aggregation state | particle |
-Sample preparation
Concentration | 8.6 mg/mL |
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Buffer | pH: 7.4 |
Vitrification | Cryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 281 K / Instrument: FEI VITROBOT MARK IV |
-Electron microscopy
Microscope | FEI TITAN KRIOS |
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Image recording | Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Number real images: 5202 / Average electron dose: 65.0 e/Å2 |
Electron beam | Acceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN |
Electron optics | Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 2.5 µm / Nominal defocus min: 0.8 µm / Nominal magnification: 105000 |
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |