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- PDB-5ovd: Ras guanine nucleotide exchange factor SOS1 (Rem-cdc25) in new cr... -

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Basic information

Entry
Database: PDB / ID: 5ovd
TitleRas guanine nucleotide exchange factor SOS1 (Rem-cdc25) in new crystal form
ComponentsSon of sevenless homolog 1
KeywordsSIGNALING PROTEIN / Guanine exchange factor / GEF / inhibitor / SOS1
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 / positive regulation of epidermal growth factor receptor signaling pathway / Regulation of KIT signaling / epidermal growth factor receptor binding / leukocyte migration / NRAGE signals death through JNK / regulation of T cell proliferation / roof of mouth development / eyelid development in camera-type eye / Fc-epsilon receptor signaling pathway / neurotrophin TRK receptor signaling pathway / GRB2:SOS provides linkage to MAPK signaling for Integrins / B cell homeostasis / 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 / SHC-related events triggered by IGF1R / Activated NTRK2 signals through FRS2 and FRS3 / Role of LAT2/NTAL/LAB on calcium mobilization / Signal attenuation / Interleukin receptor SHC signaling / 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 / SHC-mediated cascade:FGFR4 / Signaling by FGFR4 in disease / SHC-mediated cascade:FGFR1 / Erythropoietin activates RAS / FRS-mediated FGFR3 signaling / Signaling by FLT3 ITD and TKD mutants / FRS-mediated FGFR2 signaling / FRS-mediated FGFR4 signaling / Signaling by FGFR3 in disease / FRS-mediated FGFR1 signaling / Tie2 Signaling / Signaling by FGFR2 in disease / RAC1 GTPase cycle / GRB2 events in EGFR signaling / SHC1 events in EGFR signaling / myelination / EGFR Transactivation by Gastrin / Signaling by FLT3 fusion proteins / FLT3 Signaling / Signaling by FGFR1 in disease / GRB2 events in ERBB2 signaling / molecular condensate scaffold activity / NCAM signaling for neurite out-growth / 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 / insulin-like growth factor receptor signaling pathway / Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants / Antigen activates B Cell Receptor (BCR) leading to generation of second messengers / response to ischemia / axon guidance / FCERI mediated MAPK activation / Signaling by ERBB2 TMD/JMD mutants / B cell receptor signaling pathway / multicellular organism growth / Constitutive Signaling by EGFRvIII / Signaling by ERBB2 ECD mutants / epidermal growth factor receptor signaling pathway / Signaling by ERBB2 KD Mutants / Signaling by SCF-KIT / SH3 domain binding / cytokine-mediated signaling pathway / Signaling by CSF1 (M-CSF) in myeloid cells / G alpha (12/13) signalling events / Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants / DAP12 signaling / insulin receptor signaling pathway / regulation of cell population proliferation / RAF/MAP kinase cascade / Ras protein signal transduction / Potential therapeutics for SARS / protein heterodimerization activity / neuronal cell body
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. / PH domain / PH domain profile. / Pleckstrin homology domain. / Pleckstrin homology domain / Histone-fold / PH-like domain superfamily / Up-down Bundle / Orthogonal Bundle / Mainly Alpha
Similarity search - Domain/homology
Son of sevenless homolog 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.9 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
DepositionAug 28, 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 1.2Mar 6, 2019Group: Data collection / Category: reflns_shell / Item: _reflns_shell.pdbx_Rsym_value
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
A: Son of sevenless homolog 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)57,6876
Polymers57,3771
Non-polymers3105
Water6,197344
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1100 Å2
ΔGint15 kcal/mol
Surface area24770 Å2
MethodPISA
Unit cell
Length a, b, c (Å)40.941, 85.372, 176.100
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

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


Mass: 57376.637 Da / Num. of mol.: 1 / Mutation: Q560G, E561A, E562M, K563A
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: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL / Ethylene glycol


Mass: 62.068 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: C2H6O2
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 344 / 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: 2.68 Å3/Da / Density % sol: 54.14 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 7.5
Details: Protein concentration 30.7 mg/ml. Protein buffer 25 Millimolar TRIS-HCL PH 7.5, 50 millimolar NaCl, 1 millimolar DTT. Reservoir 23% (v/v) ethylenglycol. No cryo required as grown from ...Details: Protein concentration 30.7 mg/ml. Protein buffer 25 Millimolar TRIS-HCL PH 7.5, 50 millimolar NaCl, 1 millimolar DTT. Reservoir 23% (v/v) ethylenglycol. No cryo required as grown from ethylenglycol as precipitant

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: BESSY / Beamline: 14.1 / Wavelength: 0.9184 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Aug 9, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9184 Å / Relative weight: 1
ReflectionResolution: 1.9→48.37 Å / Num. obs: 49297 / % possible obs: 98.7 % / Redundancy: 4.79 % / Biso Wilson estimate: 43.44 Å2 / CC1/2: 0.999 / Rsym value: 0.06 / Net I/σ(I): 13.99
Reflection shellResolution: 1.9→2.01 Å / Redundancy: 4.87 % / Mean I/σ(I) obs: 1.46 / Num. unique obs: 7749 / CC1/2: 0.678 / Rsym value: 1.052 / % possible all: 97.6

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Processing

Software
NameVersionClassification
REFMAC5.8.0158refinement
XDSVERSION Jun 1, 2017data reduction
XDSVERSION Jun 1, 2017data scaling
PHASER2.7.17phasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2ii0

2ii0


Resolution: 1.9→48.37 Å / Cor.coef. Fo:Fc: 0.962 / Cor.coef. Fo:Fc free: 0.943 / SU B: 8.237 / SU ML: 0.119 / Cross valid method: THROUGHOUT / ESU R: 0.145 / ESU R Free: 0.14 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.24022 2101 4.3 %RANDOM
Rwork0.19866 ---
obs0.20044 47196 98.72 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 54.861 Å2
Baniso -1Baniso -2Baniso -3
1-1.98 Å20 Å2-0 Å2
2---2.37 Å20 Å2
3---0.39 Å2
Refinement stepCycle: 1 / Resolution: 1.9→48.37 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3856 0 20 344 4220
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.010.0194014
X-RAY DIFFRACTIONr_bond_other_d0.0010.023791
X-RAY DIFFRACTIONr_angle_refined_deg1.2951.9725425
X-RAY DIFFRACTIONr_angle_other_deg0.93338831
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.0445477
X-RAY DIFFRACTIONr_dihedral_angle_2_deg33.02423.762202
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.56515746
X-RAY DIFFRACTIONr_dihedral_angle_4_deg15.9511534
X-RAY DIFFRACTIONr_chiral_restr0.0760.2590
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.0214342
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02816
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_it1.5331.8891872
X-RAY DIFFRACTIONr_mcbond_other1.5171.8871871
X-RAY DIFFRACTIONr_mcangle_it2.2544.2312337
X-RAY DIFFRACTIONr_mcangle_other2.2574.2332338
X-RAY DIFFRACTIONr_scbond_it2.4552.212142
X-RAY DIFFRACTIONr_scbond_other2.4482.212142
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other3.6944.773081
X-RAY DIFFRACTIONr_long_range_B_refined7.25725.1464670
X-RAY DIFFRACTIONr_long_range_B_other7.25625.1564671
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.898→1.947 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.323 150 -
Rwork0.353 3356 -
obs--95.43 %
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)
13.7919-0.02010.67076.02251.89064.42770.09240.7387-0.9484-0.65120.18680.16920.4115-0.1154-0.27920.49410.0036-0.02020.5011-0.2030.352344.1547-9.430910.5509
21.14080.18530.05743.29370.6571.2511-0.05650.0050.0088-0.02870.0862-0.03690.0510.0613-0.02960.09880.0240.02590.27760.01450.009344.345230.746730.0576
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A560 - 744
2X-RAY DIFFRACTION2A753 - 1044

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