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- PDB-8be5: Crystal structure of SOS1-KRasG12V-Nanobody22-Nanobody75 -

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Basic information

Entry
Database: PDB / ID: 8be5
TitleCrystal structure of SOS1-KRasG12V-Nanobody22-Nanobody75
Components
  • Isoform 2B of GTPase KRas
  • Nanobody22
  • Nanobody75
  • Son of sevenless homolog 1
KeywordsSIGNALING PROTEIN / Complex / Stabilizer
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 / Activation of RAC1 ...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 / Activation of RAC1 / positive regulation of small GTPase mediated signal transduction / Signaling by LTK / blood vessel morphogenesis / epidermal growth factor receptor binding / positive regulation of epidermal growth factor receptor signaling pathway / Regulation of KIT signaling / leukocyte migration / NRAGE signals death through JNK / eyelid development in camera-type eye / Fc-epsilon receptor signaling pathway / roof of mouth development / neurotrophin TRK receptor signaling pathway / GRB2:SOS provides linkage to MAPK signaling for Integrins / B cell homeostasis / regulation of T cell proliferation / RET signaling / SOS-mediated signalling / Activated NTRK3 signals through RAS / Activated NTRK2 signals through RAS / SHC1 events in ERBB4 signaling / hair follicle development / fibroblast growth factor receptor signaling pathway / Role of LAT2/NTAL/LAB on calcium mobilization / Signalling to RAS / Interleukin receptor SHC signaling / Signal attenuation / Activated NTRK2 signals through FRS2 and FRS3 / SHC-related events triggered by IGF1R / SHC-mediated cascade:FGFR3 / MET activates RAS signaling / Schwann cell development / SHC-mediated cascade:FGFR2 / Signaling by PDGFRA transmembrane, juxtamembrane and kinase domain mutants / Signaling by PDGFRA extracellular domain mutants / SHC-mediated cascade:FGFR4 / Signaling by FGFR4 in disease / Erythropoietin activates RAS / SHC-mediated cascade:FGFR1 / FRS-mediated FGFR3 signaling / Signaling by FLT3 ITD and TKD mutants / FRS-mediated FGFR2 signaling / FRS-mediated FGFR4 signaling / Signaling by FGFR3 in disease / Tie2 Signaling / FRS-mediated FGFR1 signaling / Signaling by FGFR2 in disease / GRB2 events in EGFR signaling / SHC1 events in EGFR signaling / RAC1 GTPase cycle / Signaling by FLT3 fusion proteins / FLT3 Signaling / Signaling by FGFR1 in disease / myelination / EGFR Transactivation by Gastrin / NCAM signaling for neurite out-growth / FCERI mediated Ca+2 mobilization / GRB2 events in ERBB2 signaling / Downstream signal transduction / SHC1 events in ERBB2 signaling / Insulin receptor signalling cascade / GTPase activator activity / insulin-like growth factor receptor signaling pathway / axon guidance / Antigen activates B Cell Receptor (BCR) leading to generation of second messengers / Constitutive Signaling by Overexpressed ERBB2 / T cell activation / Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants / guanyl-nucleotide exchange factor activity / small monomeric GTPase / response to ischemia / B cell receptor signaling pathway / FCERI mediated MAPK activation / Signaling by ERBB2 TMD/JMD mutants / molecular condensate scaffold activity / Signaling by SCF-KIT / Constitutive Signaling by EGFRvIII / cytokine-mediated signaling pathway / Signaling by ERBB2 ECD mutants / multicellular organism growth / Signaling by ERBB2 KD Mutants / SH3 domain binding / epidermal growth factor receptor signaling pathway / Signaling by CSF1 (M-CSF) in myeloid cells / insulin receptor signaling pathway / DAP12 signaling / G alpha (12/13) signalling events / Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants / regulation of cell population proliferation / Ca2+ pathway / RAF/MAP kinase cascade
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-like guanine nucleotide exchange factor / Ras guanine-nucleotide exchange factors N-terminal domain profile. / Ras guanine nucleotide exchange factor domain superfamily / Ras guanine-nucleotide exchange factor, catalytic 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-like guanine nucleotide exchange factor / Ras guanine-nucleotide exchange factors N-terminal domain profile. / Ras guanine nucleotide exchange factor domain superfamily / Ras guanine-nucleotide exchange factor, catalytic 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 / : / SOS1/NGEF-like PH 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. / PH domain profile. / Pleckstrin homology domain. / Pleckstrin homology domain / Histone-fold / PH-like domain superfamily
Similarity search - Domain/homology
Isoform 2B of GTPase KRas / Son of sevenless homolog 1
Similarity search - Component
Biological speciesHomo sapiens (human)
Lama glama (llama)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3.13 Å
AuthorsFischer, B. / Wohlkonig, A. / Steyaert, J.
Funding support Belgium, 1items
OrganizationGrant numberCountry
Research Foundation - Flanders (FWO) Belgium
CitationJournal: Nat Commun / Year: 2024
Title: Allosteric nanobodies to study the interactions between SOS1 and RAS.
Authors: Fischer, B. / Uchanski, T. / Sheryazdanova, A. / Gonzalez, S. / Volkov, A.N. / Brosens, E. / Zogg, T. / Kalichuk, V. / Ballet, S. / Versees, W. / Sablina, A.A. / Pardon, E. / Wohlkonig, A. / Steyaert, J.
History
DepositionOct 21, 2022Deposition site: PDBE / Processing site: PDBE
Revision 1.0Nov 1, 2023Provider: repository / Type: Initial release
Revision 1.1Aug 14, 2024Group: 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.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Nov 6, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
AAZA: Son of sevenless homolog 1
C: Nanobody75
R: Isoform 2B of GTPase KRas
N: Nanobody22


Theoretical massNumber of molelcules
Total (without water)109,5754
Polymers109,5754
Non-polymers00
Water34219
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area6380 Å2
ΔGint-16 kcal/mol
Surface area38230 Å2
MethodPISA
Unit cell
Length a, b, c (Å)124.080, 124.080, 408.815
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number97
Space group name H-MI422
Space group name HallI42
Symmetry operation#1: x,y,z
#2: -y,x,z
#3: y,-x,z
#4: x,-y,-z
#5: -x,y,-z
#6: -x,-y,z
#7: y,x,-z
#8: -y,-x,-z
#9: x+1/2,y+1/2,z+1/2
#10: -y+1/2,x+1/2,z+1/2
#11: y+1/2,-x+1/2,z+1/2
#12: x+1/2,-y+1/2,-z+1/2
#13: -x+1/2,y+1/2,-z+1/2
#14: -x+1/2,-y+1/2,z+1/2
#15: y+1/2,x+1/2,-z+1/2
#16: -y+1/2,-x+1/2,-z+1/2

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Components

#1: Protein Son of sevenless homolog 1 / SOS-1


Mass: 59348.816 Da / Num. of mol.: 1
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
#2: Protein Nanobody75


Mass: 14658.214 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Lama glama (llama) / Production host: Escherichia coli (E. coli)
#3: Protein Isoform 2B of GTPase KRas / K-Ras 2 / Ki-Ras / c-K-ras / c-Ki-ras


Mass: 21675.314 Da / Num. of mol.: 1 / Mutation: G12V
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, small monomeric GTPase
#4: Antibody Nanobody22


Mass: 13892.469 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Lama glama (llama) / Production host: Escherichia coli (E. coli)
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 19 / Source method: isolated from a natural source / Formula: H2O
Has protein modificationY

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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: 3.65 Å3/Da / Density % sol: 66.28 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop
Details: 10% PEG 4000, 0.1 M sodium citrate, pH 5.5 and 0.2 M sodium acetate

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I24 / Wavelength: 0.96858 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Dec 15, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.96858 Å / Relative weight: 1
ReflectionResolution: 3.13→30 Å / Num. obs: 28523 / % possible obs: 99.3 % / Redundancy: 10.8 % / Biso Wilson estimate: 99.89 Å2 / CC1/2: 0.99 / Net I/σ(I): 13.65
Reflection shellResolution: 3.13→3.32 Å / Num. unique obs: 4364 / CC1/2: 0.77

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Processing

Software
NameVersionClassification
PHENIX1.20.1_4487refinement
XDSdata reduction
XDSdata scaling
PHENIXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1BKD

1bkd


Resolution: 3.13→29.91 Å / SU ML: 0.5141 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 30.5399
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2779 1426 5 %
Rwork0.226 27080 -
obs0.2286 28506 99.45 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 93.56 Å2
Refinement stepCycle: LAST / Resolution: 3.13→29.91 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6424 0 0 19 6443
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.01136553
X-RAY DIFFRACTIONf_angle_d1.38148854
X-RAY DIFFRACTIONf_chiral_restr0.0796978
X-RAY DIFFRACTIONf_plane_restr0.01241138
X-RAY DIFFRACTIONf_dihedral_angle_d16.85512482
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
3.13-3.240.39591330.38542526X-RAY DIFFRACTION94.96
3.24-3.370.3471410.30082675X-RAY DIFFRACTION99.79
3.37-3.530.36251400.28252668X-RAY DIFFRACTION99.96
3.53-3.710.32441410.27872678X-RAY DIFFRACTION99.96
3.71-3.950.28721410.23352680X-RAY DIFFRACTION99.96
3.95-4.250.26531420.21152697X-RAY DIFFRACTION100
4.25-4.680.24651430.18492716X-RAY DIFFRACTION100
4.68-5.350.24351450.19772747X-RAY DIFFRACTION100
5.35-6.730.29841460.2472777X-RAY DIFFRACTION99.97
6.73-29.910.25391540.20192916X-RAY DIFFRACTION99.84

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