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- PDB-9mjm: SOS1 IN COMPLEX WITH AN INHIBITOR -

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Basic information

Entry
Database: PDB / ID: 9mjm
TitleSOS1 IN COMPLEX WITH AN INHIBITOR
ComponentsSon of sevenless homolog 1
KeywordsONCOPROTEIN / ONCOLOGY / EXCHANGE FACTOR / PROTEIN-LIGAND COMPLEX
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 / positive regulation of epidermal growth factor receptor signaling pathway / Regulation of KIT signaling / leukocyte migration / NRAGE signals death through JNK / roof of mouth development / eyelid development in camera-type eye / Fc-epsilon receptor signaling pathway / neurotrophin TRK receptor signaling pathway / B cell homeostasis / GRB2:SOS provides linkage to MAPK signaling for Integrins / regulation of T cell proliferation / RET signaling / 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 / 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 / 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 / NCAM signaling for neurite out-growth / FCERI mediated Ca+2 mobilization / SHC1 events in ERBB2 signaling / 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 / guanyl-nucleotide exchange factor activity / response to ischemia / T cell activation / B cell receptor signaling pathway / FCERI mediated MAPK activation / epidermal growth factor receptor signaling pathway / Signaling by ERBB2 TMD/JMD mutants / molecular condensate scaffold activity / Constitutive Signaling by EGFRvIII / Signaling by SCF-KIT / Signaling by ERBB2 ECD mutants / multicellular organism growth / Signaling by ERBB2 KD Mutants / cytokine-mediated signaling pathway / SH3 domain binding / Signaling by CSF1 (M-CSF) in myeloid cells / G alpha (12/13) signalling events / insulin receptor signaling pathway / DAP12 signaling / Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants / regulation of cell population proliferation / RAF/MAP kinase cascade / Ras protein signal transduction / Potential therapeutics for SARS
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
: / IMIDAZOLE / Son of sevenless homolog 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.17 Å
AuthorsBell, J.A.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Acs Med.Chem.Lett. / Year: 2025
Title: Exploiting Solvent Exposed Salt-Bridge Interactions for the Discovery of Potent Inhibitors of SOS1 Using Free-Energy Perturbation Simulations.
Authors: Leffler, A.E. / Houang, E.M. / Gray, F. / Placzek, A.T. / Ruvinsky, A.M. / Bell, J.A. / Wang, H. / Sun, S. / Svensson, M. / Greenwood, J.R. / Frye, L.L. / Igawa, H. / Atsriku, C. / Levinson, A.M.
History
DepositionDec 16, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 2, 2025Provider: repository / Type: Initial release

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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)57,9939
Polymers57,1031
Non-polymers8908
Water5,296294
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)40.790, 85.150, 175.290
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: 57103.285 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 BL21(DE3) (bacteria) / References: UniProt: Q07889
#2: Chemical ChemComp-A1BMD / 2-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)-3-(2-oxaspiro[3.3]heptan-6-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4(3H)-one


Mass: 448.481 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C23H27F3N4O2 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: C2H6O2
#4: Chemical ChemComp-IMD / IMIDAZOLE


Mass: 69.085 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H5N2
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 294 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Has protein modificationN

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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: 2.67 Å3/Da / Density % sol: 53.85 %
Crystal growTemperature: 291 K / Method: vapor diffusion, hanging drop / Details: 0.1 M imidazole, 8% - 18% PEG 8000 / PH range: 7.5 - 8.5

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: PETRA III, DESY / Beamline: P11 / Wavelength: 1.0332 Å
DetectorType: DECTRIS EIGER2 X 16M / Detector: PIXEL / Date: Aug 24, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.0332 Å / Relative weight: 1
ReflectionResolution: 2.17→48.18 Å / Num. obs: 32970 / % possible obs: 99.2 % / Redundancy: 13.8 % / CC1/2: 0.999 / Rmerge(I) obs: 0.111 / Rpim(I) all: 0.031 / Rrim(I) all: 0.116 / Net I/σ(I): 14.1
Reflection shellResolution: 2.17→2.24 Å / Redundancy: 14.5 % / Rmerge(I) obs: 1.196 / Num. unique obs: 2836 / CC1/2: 0.825 / Rpim(I) all: 0.322 / Rrim(I) all: 1.239 / % possible all: 100

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Processing

Software
NameClassification
PRIME-Xrefinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.17→48.18 Å / Cross valid method: THROUGHOUT
RfactorNum. reflection% reflection
Rfree0.265 1647 5 %
Rwork0.207 --
obs-32969 99.2 %
Solvent computationBsol: 63.22 Å2 / ksol: 0.3208 e/Å3
Displacement parametersBiso mean: 53.7 Å2
Baniso -1Baniso -2Baniso -3
1-0.497 Å20 Å20 Å2
2---0.408 Å20 Å2
3----0.089 Å2
Refinement stepCycle: LAST / Resolution: 2.17→48.18 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3921 0 61 294 4276
Refine LS restraintsType: OPLS 2005X
LS refinement shellResolution: 2.17→2.25 Å
RfactorNum. reflection% reflection
Rfree0.366 190 5.8 %
Rwork0.31 3296 -
obs--100 %

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