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- PDB-6epo: RAS GUANINE EXCHANGE FACTOR SOS1 (REM-CDC25) IN COMPLEX WITH KRAS... -

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Basic information

Entry
Database: PDB / ID: 6epo
TitleRAS GUANINE EXCHANGE FACTOR SOS1 (REM-CDC25) IN COMPLEX WITH KRAS(G12C) AND FRAGMENT SCREENING HIT F3
Components
  • GTPase KRas
  • Son of sevenless homolog 1
KeywordsSIGNALING PROTEIN / Guanine nucleotide exchange factor / GEF / Fragment Screen / GTPASE
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
Son of sevenless (SoS) protein; Chain S, domain 1 / Son of sevenless (SoS) protein Chain: S domain 1 / Son of Sevenless (SoS) protein; Chain S, domain 2 / Ras guanine-nucleotide exchange factors catalytic 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. ...Son of sevenless (SoS) protein; Chain S, domain 1 / Son of sevenless (SoS) protein Chain: S domain 1 / Son of Sevenless (SoS) protein; Chain S, domain 2 / Ras guanine-nucleotide exchange factors catalytic 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 nucleotide triphosphate hydrolases / Up-down Bundle / P-loop containing nucleoside triphosphate hydrolase / Rossmann fold / Orthogonal Bundle / 3-Layer(aba) Sandwich / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
3-(4-chlorophenyl)propan-1-amine / GTPase KRas / Son of sevenless homolog 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 2.4 Å
AuthorsHillig, R.C. / Moosmayer, D. / Hilpmann, A. / Bader, B. / Schroeder, J. / Wortmann, L. / Sautier, B. / Kahmann, J. / Wegener, D. / Briem, H. ...Hillig, R.C. / Moosmayer, D. / Hilpmann, A. / Bader, B. / Schroeder, J. / Wortmann, L. / Sautier, B. / Kahmann, J. / Wegener, D. / Briem, H. / Petersen, K. / Badock, V.
CitationJournal: Proc. Natl. Acad. Sci. U.S.A. / Year: 2019
Title: Discovery of potent SOS1 inhibitors that block RAS activation via disruption of the RAS-SOS1 interaction.
Authors: Hillig, R.C. / Sautier, B. / Schroeder, J. / Moosmayer, D. / Hilpmann, A. / Stegmann, C.M. / Werbeck, N.D. / Briem, H. / Boemer, U. / Weiske, J. / Badock, V. / Mastouri, J. / Petersen, K. / ...Authors: Hillig, R.C. / Sautier, B. / Schroeder, J. / Moosmayer, D. / Hilpmann, A. / Stegmann, C.M. / Werbeck, N.D. / Briem, H. / Boemer, U. / Weiske, J. / Badock, V. / Mastouri, J. / Petersen, K. / Siemeister, G. / Kahmann, J.D. / Wegener, D. / Bohnke, N. / Eis, K. / Graham, K. / Wortmann, L. / von Nussbaum, F. / Bader, B.
History
DepositionOct 12, 2017Deposition site: PDBE / Processing site: PDBE
Revision 1.0Feb 6, 2019Provider: repository / Type: Initial release
Revision 1.1Feb 20, 2019Group: Data collection / Database references / Category: citation / pdbx_database_proc
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.2Jan 17, 2024Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
R: GTPase KRas
S: Son of sevenless homolog 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)76,9225
Polymers76,4902
Non-polymers4313
Water5,441302
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3490 Å2
ΔGint-11 kcal/mol
Surface area29980 Å2
MethodPISA
Unit cell
Length a, b, c (Å)150.118, 150.118, 200.087
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number97
Space group name H-MI422
Components on special symmetry positions
IDModelComponents
11S-1226-

HOH

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Components

#1: Protein GTPase KRas / K-Ras 2 / Ki-Ras / c-K-ras / c-Ki-ras


Mass: 19386.850 Da / Num. of mol.: 1 / Mutation: G12C, C118S, D126E, T127S, K128R
Source method: isolated from a genetically manipulated source
Details: N-terminal G is a cloning artifact. / Source: (gene. exp.) Homo sapiens (human) / Gene: KRAS, KRAS2, RASK2 / Production host: Escherichia coli (E. coli) / References: UniProt: P01116
#2: Protein Son of sevenless homolog 1 / SOS-1


Mass: 57103.285 Da / Num. of mol.: 1 / Mutation: K563G
Source method: isolated from a genetically manipulated source
Details: Mutation K563G is a cloning artifact / Source: (gene. exp.) Homo sapiens (human) / Gene: SOS1 / Production host: Escherichia coli (E. coli) / References: UniProt: Q07889
#3: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL / Glycerol


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#4: Chemical ChemComp-BPW / 3-(4-chlorophenyl)propan-1-amine


Mass: 169.651 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C9H12ClN / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 302 / Source method: isolated from a natural source / Formula: H2O

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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: 3.68 Å3/Da / Density % sol: 66.62 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 6.5
Details: Drops made from KRAS SOS1 complex (14.4 mg/ml in 5 mM Tris pH 7.5, 100mM NaCl) and reservoir solution (2.9 to 3.4 M sodium formate, 100 mM MES pH 6.5). Fragment soaked at 25 mM for two days ...Details: Drops made from KRAS SOS1 complex (14.4 mg/ml in 5 mM Tris pH 7.5, 100mM NaCl) and reservoir solution (2.9 to 3.4 M sodium formate, 100 mM MES pH 6.5). Fragment soaked at 25 mM for two days using a 500 mM fragment stock solution in DMSO. Cryo buffer 0.1 M MES pH 6.5, 3.5 M sodium formate, 20 glycerol, 25 mM fragment

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID09 / Wavelength: 0.97718 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jul 18, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97718 Å / Relative weight: 1
ReflectionResolution: 2.4→48.54 Å / Num. obs: 469504 / % possible obs: 99.9 % / Redundancy: 10.5 % / Biso Wilson estimate: 54.7 Å2 / CC1/2: 0.998 / Rsym value: 0.115 / Net I/σ(I): 13.9
Reflection shellResolution: 2.4→2.54 Å / Redundancy: 10.6 % / Mean I/σ(I) obs: 2.3 / Num. unique obs: 7135 / CC1/2: 0.766 / Rsym value: 0.924 / % possible all: 99.8

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Processing

Software
NameVersionClassification
REFMAC5.8.0158refinement
XDSVERSION Jun 17, 2015data reduction
XDSVERSION Jun 17, 2015data scaling
REFMACphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS
Starting model: 1bkd

1bkd


Resolution: 2.4→48.54 Å / Cor.coef. Fo:Fc: 0.961 / Cor.coef. Fo:Fc free: 0.952 / SU B: 12.458 / SU ML: 0.143 / Cross valid method: THROUGHOUT / ESU R: 0.232 / ESU R Free: 0.186 / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.21363 1736 3.9 %RANDOM
Rwork0.18629 ---
obs0.18736 43123 99.95 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso mean: 58.224 Å2
Baniso -1Baniso -2Baniso -3
1--0.45 Å2-0 Å2-0 Å2
2---0.45 Å2-0 Å2
3---0.9 Å2
Refinement stepCycle: 1 / Resolution: 2.4→48.54 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5156 0 28 302 5486
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0090.0195330
X-RAY DIFFRACTIONr_bond_other_d0.0020.025008
X-RAY DIFFRACTIONr_angle_refined_deg1.3481.9697197
X-RAY DIFFRACTIONr_angle_other_deg0.9743.00111623
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.7565629
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.72423.82267
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.82115986
X-RAY DIFFRACTIONr_dihedral_angle_4_deg16.2851544
X-RAY DIFFRACTIONr_chiral_restr0.080.2785
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.0215791
X-RAY DIFFRACTIONr_gen_planes_other0.0010.021081
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it3.5633.7352511
X-RAY DIFFRACTIONr_mcbond_other3.5613.7342510
X-RAY DIFFRACTIONr_mcangle_it5.5918.3753134
X-RAY DIFFRACTIONr_mcangle_other5.5918.3793135
X-RAY DIFFRACTIONr_scbond_it4.5254.2772819
X-RAY DIFFRACTIONr_scbond_other4.5244.282820
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other7.1269.3024061
X-RAY DIFFRACTIONr_long_range_B_refined9.47946.0725979
X-RAY DIFFRACTIONr_long_range_B_other9.4846.0845980
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.4→2.462 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.447 126 -
Rwork0.389 3124 -
obs--99.97 %
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
11.79330.1670.04774.9764-0.59841.81090.03740.1176-0.0012-0.1078-0.0975-0.2293-0.13020.27610.06010.0769-0.03930.0240.0966-0.00560.0202178.894141.214261.847
25.59010.8407-1.61763.02250.40823.7695-0.11850.7222-0.4793-0.5763-0.1159-0.1037-0.0096-0.33050.23440.26050.06870.01170.2245-0.08930.0516162.75118.871225.856
30.8794-0.09980.34791.1395-0.77163.1356-0.0332-0.0267-0.1364-0.0391-0.0039-0.05920.25630.06110.03710.050.01860.01470.03040.0010.0287172.503115.602267.789
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1R1 - 169
2X-RAY DIFFRACTION2S565 - 743
3X-RAY DIFFRACTION3S752 - 1046

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