+Open data
-Basic information
Entry | Database: PDB / ID: 7kfz | ||||||
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Title | Structure of a ternary KRas(G13D)-SOS complex | ||||||
Components |
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Keywords | HYDROLASE/SIGNALING PROTEIN / 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 / Interleukin-15 signaling / positive regulation of small GTPase mediated signal transduction ...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 / Interleukin-15 signaling / positive regulation of small GTPase mediated signal transduction / Activation of RAC1 / blood vessel morphogenesis / Signaling by LTK / forebrain astrocyte development / Regulation of KIT signaling / positive regulation of epidermal growth factor receptor signaling pathway / negative regulation of epithelial cell differentiation / NRAGE signals death through JNK / regulation of synaptic transmission, GABAergic / epidermal growth factor receptor binding / epithelial tube branching involved in lung morphogenesis / type I pneumocyte differentiation / leukocyte migration / regulation of T cell proliferation / roof of mouth development / Rac protein signal transduction / eyelid development in camera-type eye / positive regulation of Rac protein signal transduction / skeletal muscle cell differentiation / Fc-epsilon receptor signaling pathway / Signaling by RAS GAP mutants / Signaling by RAS GTPase mutants / Activation of RAS in B cells / GRB2:SOS provides linkage to MAPK signaling for Integrins / neurotrophin TRK receptor signaling pathway / B cell homeostasis / RAS signaling downstream of NF1 loss-of-function variants / RUNX3 regulates p14-ARF / RET signaling / SOS-mediated signalling / 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 / Signal attenuation / Interleukin receptor SHC signaling / Estrogen-stimulated signaling through PRKCZ / SHC-mediated cascade:FGFR3 / MET activates RAS signaling / Schwann cell development / 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 / positive regulation of glial cell proliferation / FRS-mediated FGFR3 signaling / Signaling by CSF3 (G-CSF) / Signaling by FLT3 ITD and TKD mutants / 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 / 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 / myelination / FLT3 Signaling / Signaling by FGFR1 in disease / Ras activation upon Ca2+ influx through NMDA receptor / GRB2 events in ERBB2 signaling / CD209 (DC-SIGN) signaling / NCAM signaling for neurite out-growth / SHC1 events in ERBB2 signaling / GTPase activator activity / Downstream signal transduction / Constitutive Signaling by Overexpressed ERBB2 / Insulin receptor signalling cascade / FCERI mediated Ca+2 mobilization / T cell activation / guanyl-nucleotide exchange factor activity / Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants / insulin-like growth factor receptor signaling pathway Similarity search - Function | ||||||
Biological species | Homo sapiens (human) | ||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.47 Å | ||||||
Authors | Liu, C. / Moghadamchargari, Z. / Laganowsky, A. / Zhao, M. | ||||||
Funding support | United States, 1items
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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 | Molecule: MolmilJmol/JSmol |
-Downloads & links
-Download
PDBx/mmCIF format | 7kfz.cif.gz | 159.3 KB | Display | PDBx/mmCIF format |
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PDB format | pdb7kfz.ent.gz | 121.4 KB | Display | PDB format |
PDBx/mmJSON format | 7kfz.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Summary document | 7kfz_validation.pdf.gz | 1.1 MB | Display | wwPDB validaton report |
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Full document | 7kfz_full_validation.pdf.gz | 1.1 MB | Display | |
Data in XML | 7kfz_validation.xml.gz | 33.8 KB | Display | |
Data in CIF | 7kfz_validation.cif.gz | 52.4 KB | Display | |
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/kf/7kfz ftp://data.pdbj.org/pub/pdb/validation_reports/kf/7kfz | HTTPS FTP |
-Related structure data
Related structure data | 22857MC M: map data used to model this data 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
-Assembly
Deposited unit |
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1 |
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-Components
#1: Protein | Mass: 19386.848 Da / Num. of mol.: 2 / Mutation: G13D 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, small monomeric GTPase #2: Protein | | Mass: 57449.691 Da / Num. of mol.: 1 / Fragment: UNP residues 564-1049 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: SOS1 / Production host: Escherichia coli (E. coli) / References: UniProt: Q07889 #3: Chemical | ChemComp-GNP / | #4: Chemical | ChemComp-MG / | Has ligand of interest | N | |
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-Experimental details
-Experiment
Experiment | Method: ELECTRON MICROSCOPY |
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EM experiment | Aggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction |
-Sample preparation
Component | Name: A ternary complex of KRas(G13D) and SOScat / Type: COMPLEX / Entity ID: #1-#2 / Source: RECOMBINANT |
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Molecular weight | Value: 0.0967 MDa / Experimental value: YES |
Source (natural) | Organism: Homo sapiens (human) |
Source (recombinant) | Organism: Escherichia coli (E. coli) |
Buffer solution | pH: 7.4 |
Specimen | Conc.: 8.6 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES |
Vitrification | Instrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 281 K |
-Electron microscopy imaging
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |
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Microscopy | Model: FEI TITAN KRIOS |
Electron gun | Electron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM |
Electron lens | Mode: BRIGHT FIELD / Nominal magnification: 105000 X / Nominal defocus max: 2500 nm / Nominal defocus min: 800 nm / Cs: 2.7 mm |
Image recording | Electron dose: 65 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Num. of real images: 5202 |
-Processing
Software | Name: PHENIX / Version: 1.18.2_3874: / Classification: refinement | ||||||||||||||||||||||||||||||||
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EM software |
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CTF correction | Type: PHASE FLIPPING ONLY | ||||||||||||||||||||||||||||||||
Particle selection | Num. of particles selected: 5749548 | ||||||||||||||||||||||||||||||||
Symmetry | Point symmetry: C1 (asymmetric) | ||||||||||||||||||||||||||||||||
3D reconstruction | Resolution: 3.47 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 1021288 / Symmetry type: POINT | ||||||||||||||||||||||||||||||||
Atomic model building | B value: 50 / Protocol: AB INITIO MODEL / Space: REAL | ||||||||||||||||||||||||||||||||
Atomic model building | PDB-ID: 1XD2 Accession code: 1XD2 / Source name: PDB / Type: experimental model | ||||||||||||||||||||||||||||||||
Refine LS restraints |
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