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- PDB-5ovh: Ras guanine nucleotide exchange factor SOS1 (Rem-cdc25) in comple... -

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Basic information

Entry
Database: PDB / ID: 5ovh
TitleRas guanine nucleotide exchange factor SOS1 (Rem-cdc25) in complex with small molecule inhibitor compound 21
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 / 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 / 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 / RAF/MAP kinase cascade / Potential therapeutics for SARS / Ras protein signal transduction
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. / 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
Chem-AWW / Son of sevenless homolog 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.3 Å
AuthorsHillig, R.C. / Sautier, B. / Schroeder, J. / Moosmayer, D. / Hilpmann, A. / Stegmann, C.M. / Briem, H. / Boemer, U. / Weiske, J. / Badock, V. ...Hillig, R.C. / Sautier, B. / Schroeder, J. / Moosmayer, D. / Hilpmann, A. / Stegmann, C.M. / Briem, H. / Boemer, U. / Weiske, J. / Badock, V. / Petersen, K. / Kahmann, J. / Wegener, D. / Bohnke, N. / Eis, K. / Graham, K. / Wortmann, L. / von Nussbaum, F. / Bader, B.
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 1.2Jan 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

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Assembly

Deposited unit
A: Son of sevenless homolog 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)57,9384
Polymers57,3771
Non-polymers5623
Water5,693316
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area420 Å2
ΔGint6 kcal/mol
Surface area24090 Å2
MethodPISA
Unit cell
Length a, b, c (Å)41.413, 85.362, 176.221
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-AWW / [2-[5-[(1~{R})-1-[(6,7-dimethoxy-2-methyl-5,8-dihydroquinazolin-4-yl)amino]ethyl]thiophen-2-yl]phenyl]methanol


Mass: 437.554 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C24H27N3O3S
#3: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C2H6O2
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 316 / 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: 2.71 Å3/Da / Density % sol: 54.69 %
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. Protein incubated with 5 MILLIMOLAR ...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. Protein incubated with 5 MILLIMOLAR LIGAND overnight at 277K prior to crystallization.

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: BESSY / Beamline: 14.1 / Wavelength: 0.91841 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Aug 20, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.91841 Å / Relative weight: 1
ReflectionResolution: 2.3→48.4 Å / Num. obs: 28560 / % possible obs: 99.5 % / Redundancy: 5.3 % / Biso Wilson estimate: 45.4 Å2 / CC1/2: 0.999 / Rsym value: 0.051 / Net I/σ(I): 22.13
Reflection shellResolution: 2.3→2.44 Å / Redundancy: 5.33 % / Mean I/σ(I) obs: 4.86 / Num. unique obs: 4505 / CC1/2: 0.94 / Rsym value: 0.328 / % possible all: 98.8

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Processing

Software
NameVersionClassification
REFMAC5.8.0135refinement
XDSVersion March 1, 2015data reduction
XDSVersion March 1, 2015data scaling
MOLREPversion 11.0.02phasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2ii0

2ii0


Resolution: 2.3→44.06 Å / Cor.coef. Fo:Fc: 0.894 / Cor.coef. Fo:Fc free: 0.813 / SU B: 10.081 / SU ML: 0.246 / Cross valid method: THROUGHOUT / ESU R: 0.38 / ESU R Free: 0.302 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.33022 1429 5 %RANDOM
Rwork0.25969 ---
obs0.26324 27149 99.59 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 49.569 Å2
Baniso -1Baniso -2Baniso -3
1-3.86 Å20 Å2-0 Å2
2---1.98 Å2-0 Å2
3----1.88 Å2
Refinement stepCycle: 1 / Resolution: 2.3→44.06 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3778 0 39 316 4133
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0070.0193907
X-RAY DIFFRACTIONr_bond_other_d0.0010.023789
X-RAY DIFFRACTIONr_angle_refined_deg1.0981.9785276
X-RAY DIFFRACTIONr_angle_other_deg0.8633.0018704
X-RAY DIFFRACTIONr_dihedral_angle_1_deg4.8285451
X-RAY DIFFRACTIONr_dihedral_angle_2_deg31.78723.646192
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.4315718
X-RAY DIFFRACTIONr_dihedral_angle_4_deg11.6811532
X-RAY DIFFRACTIONr_chiral_restr0.0580.2571
X-RAY DIFFRACTIONr_gen_planes_refined0.0030.0214283
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02894
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_it3.2294.7521816
X-RAY DIFFRACTIONr_mcbond_other3.2234.7481815
X-RAY DIFFRACTIONr_mcangle_it5.12310.6582263
X-RAY DIFFRACTIONr_mcangle_other5.12210.6652264
X-RAY DIFFRACTIONr_scbond_it3.175.1032091
X-RAY DIFFRACTIONr_scbond_other3.1675.1032091
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other5.22911.2313014
X-RAY DIFFRACTIONr_long_range_B_refined7.71228.6654623
X-RAY DIFFRACTIONr_long_range_B_other7.71128.6664624
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.3→2.36 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.369 103 -
Rwork0.32 1947 -
obs--99.66 %

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