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

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Basic information

Entry
Database: PDB / ID: 6epp
TitleRAS GUANINE EXCHANGE FACTOR SOS1 (REM-CDC25) IN COMPLEX WITH KRAS(G12C) AND FRAGMENT SCREENING HIT F4
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 / 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 / Signaling by LTK / blood vessel morphogenesis / epidermal growth factor receptor binding / forebrain astrocyte development / positive regulation of epidermal growth factor receptor signaling pathway / Regulation of KIT signaling / leukocyte migration / negative regulation of epithelial cell differentiation / NRAGE signals death through JNK / type I pneumocyte differentiation / regulation of synaptic transmission, GABAergic / epithelial tube branching involved in lung morphogenesis / roof of mouth development / eyelid development in camera-type eye / Rac protein signal transduction / Fc-epsilon receptor signaling pathway / skeletal muscle cell differentiation / positive regulation of Rac protein signal transduction / neurotrophin TRK receptor signaling pathway / B cell homeostasis / Signaling by RAS GAP mutants / Signaling by RAS GTPase mutants / GRB2:SOS provides linkage to MAPK signaling for Integrins / Activation of RAS in B cells / regulation of T cell proliferation / RAS signaling downstream of NF1 loss-of-function variants / RET signaling / RUNX3 regulates p14-ARF / SOS-mediated signalling / Activated NTRK3 signals through RAS / Activated NTRK2 signals through RAS / hair follicle development / SHC1 events in ERBB4 signaling / 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 / glial cell proliferation / Estrogen-stimulated signaling through PRKCZ / SHC-mediated cascade:FGFR3 / MET activates RAS signaling / Schwann cell development / PTK6 Regulates RHO GTPases, RAS GTPase and MAP kinases / 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 CSF3 (G-CSF) / membrane-membrane adaptor activity / Signaling by FLT3 ITD and TKD mutants / positive regulation of glial cell proliferation / FRS-mediated FGFR2 signaling / FRS-mediated FGFR4 signaling / homeostasis of number of cells within a tissue / Signaling by FGFR3 in disease / p38MAPK events / Tie2 Signaling / FRS-mediated FGFR1 signaling / Signaling by FGFR2 in disease / striated muscle cell differentiation / GRB2 events in EGFR signaling / SHC1 events in EGFR signaling / EGFR Transactivation by Gastrin / RAC1 GTPase cycle / Signaling by FLT3 fusion proteins / FLT3 Signaling / Signaling by FGFR1 in disease / myelination / GRB2 events in ERBB2 signaling / CD209 (DC-SIGN) signaling / NCAM signaling for neurite out-growth / FCERI mediated Ca+2 mobilization / SHC1 events in ERBB2 signaling / Ras activation upon Ca2+ influx through NMDA receptor / Downstream signal transduction / 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 / Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants
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-like guanine nucleotide exchange factor ...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-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. / Small GTPase, Ras-type / small GTPase Ras family profile. / Ran (Ras-related nuclear proteins) /TC4 subfamily of small GTPases / 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
Chem-BOQ / 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 1.2Aug 14, 2019Group: Data collection / Category: reflns / reflns_shell
Item: _reflns.pdbx_Rrim_I_all / _reflns_shell.pdbx_Rrim_I_all
Revision 1.3Jan 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)76,8084
Polymers76,4902
Non-polymers3172
Water5,386299
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3470 Å2
ΔGint-12 kcal/mol
Surface area29960 Å2
MethodPISA
Unit cell
Length a, b, c (Å)149.980, 149.980, 200.370
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number97
Space group name H-MI422

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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


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#4: Chemical ChemComp-BOQ / ethyl 2-(aminomethyl)-5-~{tert}-butyl-furan-3-carboxylate


Mass: 225.284 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C12H19NO3 / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 299 / 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: 66.6 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop
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 three ...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 three days at 277 K 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: ID29 / Wavelength: 0.9762 Å
DetectorType: DECTRIS PILATUS 6M-F / Detector: PIXEL / Date: Jul 9, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9762 Å / Relative weight: 1
ReflectionResolution: 2.4→47.43 Å / Num. obs: 44844 / % possible obs: 99.9 % / Redundancy: 9.5 % / Biso Wilson estimate: 47.3 Å2 / CC1/2: 0.998 / Rrim(I) all: 0.113 / Net I/av σ(I): 17.4 / Net I/σ(I): 17.4
Reflection shellResolution: 2.4→2.54 Å / Redundancy: 9.7 % / Mean I/σ(I) obs: 2.5 / Num. unique obs: 7124 / CC1/2: 0.895 / Rrim(I) all: 0.845 / % possible all: 99.9

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Processing

Software
NameVersionClassification
REFMAC5.8.0158refinement
XDSdata reduction
XDSdata scaling
REFMACphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS
Starting model: 1BKD

1bkd


Resolution: 2.4→47.43 Å / Cor.coef. Fo:Fc: 0.961 / Cor.coef. Fo:Fc free: 0.955 / SU B: 11.549 / SU ML: 0.132 / Cross valid method: THROUGHOUT / ESU R: 0.225 / ESU R Free: 0.176 / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.20076 2165 4.8 %RANDOM
Rwork0.17728 ---
obs0.17843 42657 99.93 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso mean: 53.999 Å2
Baniso -1Baniso -2Baniso -3
1--0.51 Å20 Å2-0 Å2
2---0.51 Å20 Å2
3---1.03 Å2
Refinement stepCycle: 1 / Resolution: 2.4→47.43 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5163 0 22 299 5484
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.010.0195355
X-RAY DIFFRACTIONr_bond_other_d0.0020.025022
X-RAY DIFFRACTIONr_angle_refined_deg1.5171.9697241
X-RAY DIFFRACTIONr_angle_other_deg1.0113.00111663
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.7235635
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.53123.792269
X-RAY DIFFRACTIONr_dihedral_angle_3_deg17.9715989
X-RAY DIFFRACTIONr_dihedral_angle_4_deg17.5961545
X-RAY DIFFRACTIONr_chiral_restr0.0880.2789
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.0215843
X-RAY DIFFRACTIONr_gen_planes_other0.0020.021090
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_it3.4353.3312528
X-RAY DIFFRACTIONr_mcbond_other3.4313.3282527
X-RAY DIFFRACTIONr_mcangle_it5.5767.4513161
X-RAY DIFFRACTIONr_mcangle_other5.5767.4573162
X-RAY DIFFRACTIONr_scbond_it4.5023.8942827
X-RAY DIFFRACTIONr_scbond_other4.5013.8962828
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other7.2168.4254079
X-RAY DIFFRACTIONr_long_range_B_refined11.06663.25521984
X-RAY DIFFRACTIONr_long_range_B_other11.06463.24921983
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
Rfree0.321 168 -
Rwork0.291 3090 -
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)
11.32590.264-0.09383.5503-0.59821.864-0.00840.0509-0.0059-0.0458-0.0665-0.1845-0.07980.29030.07480.0947-0.04220.01150.12250.0030.0124178.769141.115262.199
24.09080.5748-1.35312.42580.65873.013-0.10430.6725-0.3096-0.5228-0.1043-0.0082-0.1148-0.31780.20860.28410.07070.00150.2725-0.08110.033162.636118.788226.16
30.8094-0.06270.26631.0007-0.43882.2566-0.0269-0.0725-0.10370.00620.0123-0.05120.23630.03850.01460.12540.03740.01430.1059-0.00590.0214172.383115.522268.148
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1R1 - 167
2X-RAY DIFFRACTION2S568 - 743
3X-RAY DIFFRACTION3S752 - 1044

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