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- EMDB-22857: Structure of a ternary KRas(G13D)-SOS complex -

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Entry
Database: EMDB / ID: EMD-22857
TitleStructure of a ternary KRas(G13D)-SOS complex
Map data
Sample
  • Complex: A ternary complex of KRas(G13D) and SOScat
    • Protein or peptide: GTPase KRas
    • Protein or peptide: Son of sevenless homolog 1
  • Ligand: PHOSPHOAMINOPHOSPHONIC ACID-GUANYLATE ESTER
  • Ligand: MAGNESIUM ION
KeywordsRas / 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 / regulation of synaptic transmission, GABAergic / negative regulation of epithelial cell differentiation / epithelial tube branching involved in lung morphogenesis / Regulation of KIT signaling / epidermal growth factor receptor binding / type I pneumocyte differentiation / leukocyte migration / NRAGE signals death through JNK / regulation of T cell proliferation / 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 / Fc-epsilon receptor signaling pathway / Signaling by RAS GAP mutants / Signaling by RAS GTPase mutants / Activation of RAS in B cells / neurotrophin TRK receptor signaling pathway / GRB2:SOS provides linkage to MAPK signaling for Integrins / B cell homeostasis / RAS signaling downstream of NF1 loss-of-function variants / RUNX3 regulates p14-ARF / SOS-mediated signalling / Activated NTRK3 signals through RAS / RET signaling / Activated NTRK2 signals through RAS / hair follicle development / SHC1 events in ERBB4 signaling / Signalling to RAS / fibroblast growth factor receptor signaling pathway / glial cell proliferation / SHC-related events triggered by IGF1R / Activated NTRK2 signals through FRS2 and FRS3 / Role of LAT2/NTAL/LAB on calcium mobilization / Signal attenuation / Estrogen-stimulated signaling through PRKCZ / Interleukin receptor SHC signaling / SHC-mediated cascade:FGFR3 / MET activates RAS signaling / PTK6 Regulates RHO GTPases, RAS GTPase and MAP kinases / Schwann cell development / 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 / RAC1 GTPase cycle / GRB2 events in EGFR signaling / striated muscle cell differentiation / SHC1 events in EGFR signaling / myelination / 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 / molecular condensate scaffold activity / NCAM signaling for neurite out-growth / CD209 (DC-SIGN) signaling / GTPase activator activity / SHC1 events in ERBB2 signaling / Downstream signal transduction / Insulin receptor signalling cascade / Constitutive Signaling by Overexpressed ERBB2 / FCERI mediated Ca+2 mobilization / guanyl-nucleotide exchange factor activity / small monomeric GTPase / G protein activity / insulin-like growth factor receptor signaling pathway
Similarity search - Function
Ras guanine-nucleotide exchange factor, conserved site / Ras Guanine-nucleotide exchange factors domain signature. / RasGEF N-terminal motif / Guanine nucleotide exchange factor for Ras-like GTPases; N-terminal motif / Ras-like guanine nucleotide exchange factor, N-terminal / Ras guanine-nucleotide exchange factors N-terminal domain profile. / Ras-like guanine nucleotide exchange factor / Ras guanine-nucleotide exchange factor, catalytic domain superfamily / Ras guanine nucleotide exchange factor domain superfamily / RasGEF domain ...Ras guanine-nucleotide exchange factor, conserved site / Ras Guanine-nucleotide exchange factors domain signature. / RasGEF N-terminal motif / Guanine nucleotide exchange factor for Ras-like GTPases; N-terminal motif / Ras-like guanine nucleotide exchange factor, N-terminal / Ras guanine-nucleotide exchange factors N-terminal domain profile. / Ras-like guanine nucleotide exchange factor / Ras guanine-nucleotide exchange factor, catalytic domain superfamily / Ras guanine nucleotide exchange factor domain superfamily / RasGEF domain / Ras guanine-nucleotide exchange factors catalytic domain profile. / Guanine nucleotide exchange factor for Ras-like small GTPases / Ras guanine-nucleotide exchange factors catalytic domain / Dbl homology (DH) domain superfamily / RhoGEF domain / Guanine nucleotide exchange factor for Rho/Rac/Cdc42-like GTPases / Dbl homology (DH) domain / Dbl homology (DH) domain profile. / Small GTPase, Ras-type / small GTPase Ras family profile. / Ran (Ras-related nuclear proteins) /TC4 subfamily of small GTPases / PH domain / PH domain profile. / Pleckstrin homology domain. / Pleckstrin homology domain / Rho (Ras homology) subfamily of Ras-like small GTPases / Ras subfamily of RAS small GTPases / Small GTPase / Ras family / Rab subfamily of small GTPases / Histone-fold / Small GTP-binding protein domain / PH-like domain superfamily / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
GTPase KRas / Son of sevenless homolog 1
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.47 Å
AuthorsLiu C / Moghadamchargari Z
Funding support United States, 1 items
OrganizationGrant numberCountry
National Institutes of Health/National Cancer Institute (NIH/NCI)RO1GM121751 United States
CitationJournal: 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
DepositionOct 15, 2020-
Header (metadata) releaseMar 31, 2021-
Map releaseMar 31, 2021-
UpdateMar 6, 2024-
Current statusMar 6, 2024Processing site: RCSB / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.014
  • Imaged by UCSF Chimera
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  • Surface view colored by radius
  • Surface level: 0.014
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  • Surface view with fitted model
  • Atomic models: PDB-7kfz
  • Surface level: 0.014
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_22857.png

Downloads & links

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Map

FileDownload / File: emd_22857.map.gz / Format: CCP4 / Size: 27 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Voxel sizeX=Y=Z: 1.065 Å
Density
Contour LevelBy AUTHOR: 0.01 / Movie #1: 0.014
Minimum - Maximum-0.014432735 - 0.06480882
Average (Standard dev.)0.00017181902 (±0.002492705)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions192192192
Spacing192192192
CellA=B=C: 204.48001 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.0651.0651.065
M x/y/z192192192
origin x/y/z0.0000.0000.000
length x/y/z204.480204.480204.480
α/β/γ90.00090.00090.000
start NX/NY/NZ000
NX/NY/NZ400400400
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS192192192
D min/max/mean-0.0140.0650.000

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Supplemental data

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Mask #1

Fileemd_22857_msk_1.map
Projections & Slices
AxesZYX

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Additional map: #1

Fileemd_22857_additional_1.map
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Half map: #1

Fileemd_22857_half_map_1.map
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Half map: #2

Fileemd_22857_half_map_2.map
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Sample components

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Entire : A ternary complex of KRas(G13D) and SOScat

EntireName: A ternary complex of KRas(G13D) and SOScat
Components
  • Complex: A ternary complex of KRas(G13D) and SOScat
    • Protein or peptide: GTPase KRas
    • Protein or peptide: Son of sevenless homolog 1
  • Ligand: PHOSPHOAMINOPHOSPHONIC ACID-GUANYLATE ESTER
  • Ligand: MAGNESIUM ION

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Supramolecule #1: A ternary complex of KRas(G13D) and SOScat

SupramoleculeName: A ternary complex of KRas(G13D) and SOScat / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#2
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 96.7 KDa

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Macromolecule #1: GTPase KRas

MacromoleculeName: GTPase KRas / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO / EC number: small monomeric GTPase
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 19.386848 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString:
GMTEYKLVVV GAGDVGKSAL TIQLIQNHFV DEYDPTIEDS YRKQVVIDGE TCLLDILDTA GQEEYSAMRD QYMRTGEGFL CVFAINNTK SFEDIHHYRE QIKRVKDSED VPMVLVGNKC DLPSRTVDTK QAQDLARSYG IPFIETSAKT RQGVDDAFYT L VREIRKHK EK

UniProtKB: GTPase KRas

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Macromolecule #2: Son of sevenless homolog 1

MacromoleculeName: Son of sevenless homolog 1 / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 57.449691 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString: 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

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Macromolecule #3: PHOSPHOAMINOPHOSPHONIC ACID-GUANYLATE ESTER

MacromoleculeName: PHOSPHOAMINOPHOSPHONIC ACID-GUANYLATE ESTER / type: ligand / ID: 3 / Number of copies: 1 / Formula: GNP
Molecular weightTheoretical: 522.196 Da
Chemical component information

ChemComp-GNP:
PHOSPHOAMINOPHOSPHONIC ACID-GUANYLATE ESTER / GppNHp, GMPPNP, energy-carrying molecule analogue*YM / 5'-Guanylyl imidodiphosphate

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Macromolecule #4: MAGNESIUM ION

MacromoleculeName: MAGNESIUM ION / type: ligand / ID: 4 / Number of copies: 1 / Formula: MG
Molecular weightTheoretical: 24.305 Da

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

Concentration8.6 mg/mL
BufferpH: 7.4
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 281 K / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy / Cs: 2.7 mm / Nominal defocus max: 2.5 µm / Nominal defocus min: 0.8 µm / Nominal magnification: 105000
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Number real images: 5202 / Average electron dose: 65.0 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 5749548
Startup modelType of model: PDB ENTRY
PDB model - PDB ID:

1xd2

Initial angle assignmentType: RANDOM ASSIGNMENT / Software - Name: RELION (ver. 3.1)
Final 3D classificationNumber classes: 3 / Software - Name: RELION (ver. 3.1)
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: RELION (ver. 3.1)
Final reconstructionApplied symmetry - Point group: C1 (asymmetric) / Resolution.type: BY AUTHOR / Resolution: 3.47 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION / Number images used: 1021288
FSC plot (resolution estimation)

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Atomic model buiding 1

Initial modelPDB ID:

1xd2


Chain - Source name: PDB / Chain - Initial model type: experimental model
RefinementSpace: REAL / Protocol: AB INITIO MODEL / Overall B value: 50
Output model

PDB-7kfz:
Structure of a ternary KRas(G13D)-SOS complex

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