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- PDB-6scm: SOS1 in Complex with Inhibitor BI-3406 -

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Basic information

Entry
Database: PDB / ID: 6scm
TitleSOS1 in Complex with Inhibitor BI-3406
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 / blood vessel morphogenesis / Signaling by LTK / epidermal growth factor receptor binding / Regulation of KIT signaling / positive regulation of epidermal growth factor receptor signaling pathway / leukocyte migration / NRAGE signals death through JNK / neurotrophin TRK receptor signaling pathway / Fc-epsilon receptor signaling pathway / eyelid development in camera-type eye / GRB2:SOS provides linkage to MAPK signaling for Integrins / roof of mouth development / regulation of T cell proliferation / B cell homeostasis / RET signaling / SOS-mediated signalling / Activated NTRK3 signals through RAS / Activated NTRK2 signals through RAS / fibroblast growth factor receptor signaling pathway / Role of LAT2/NTAL/LAB on calcium mobilization / SHC1 events in ERBB4 signaling / Interleukin receptor SHC signaling / hair follicle development / Signalling to RAS / Signal attenuation / Activated NTRK2 signals through FRS2 and FRS3 / SHC-related events triggered by IGF1R / Schwann cell development / SHC-mediated cascade:FGFR3 / MET activates RAS signaling / SHC-mediated cascade:FGFR2 / Signaling by PDGFRA transmembrane, juxtamembrane and kinase domain mutants / Signaling by PDGFRA extracellular domain mutants / SHC-mediated cascade:FGFR4 / Erythropoietin activates RAS / SHC-mediated cascade:FGFR1 / Signaling by FGFR4 in disease / FRS-mediated FGFR3 signaling / Signaling by FLT3 ITD and TKD mutants / FRS-mediated FGFR2 signaling / FRS-mediated FGFR4 signaling / FRS-mediated FGFR1 signaling / Signaling by FGFR3 in disease / Tie2 Signaling / Signaling by FGFR2 in disease / RAC1 GTPase cycle / myelination / GRB2 events in EGFR signaling / SHC1 events in EGFR signaling / Signaling by FLT3 fusion proteins / FLT3 Signaling / Signaling by FGFR1 in disease / EGFR Transactivation by Gastrin / FCERI mediated Ca+2 mobilization / NCAM signaling for neurite out-growth / GRB2 events in ERBB2 signaling / Downstream signal transduction / Insulin receptor signalling cascade / insulin-like growth factor receptor signaling pathway / SHC1 events in ERBB2 signaling / GTPase activator activity / 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 / T cell activation / response to ischemia / B cell receptor signaling pathway / FCERI mediated MAPK activation / molecular condensate scaffold activity / Signaling by ERBB2 TMD/JMD mutants / Signaling by SCF-KIT / Constitutive Signaling by EGFRvIII / Signaling by ERBB2 ECD mutants / Signaling by ERBB2 KD Mutants / SH3 domain binding / multicellular organism growth / epidermal growth factor receptor signaling pathway / cytokine-mediated 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
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 / Chem-L7H / Son of sevenless homolog 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.866 Å
AuthorsKessler, D. / Fischer, G. / Ramharter, J.
CitationJournal: Cancer Discov / Year: 2021
Title: BI-3406, a Potent and Selective SOS1-KRAS Interaction Inhibitor, Is Effective in KRAS-Driven Cancers through Combined MEK Inhibition.
Authors: Hofmann, M.H. / Gmachl, M. / Ramharter, J. / Savarese, F. / Gerlach, D. / Marszalek, J.R. / Sanderson, M.P. / Kessler, D. / Trapani, F. / Arnhof, H. / Rumpel, K. / Botesteanu, D.A. / ...Authors: Hofmann, M.H. / Gmachl, M. / Ramharter, J. / Savarese, F. / Gerlach, D. / Marszalek, J.R. / Sanderson, M.P. / Kessler, D. / Trapani, F. / Arnhof, H. / Rumpel, K. / Botesteanu, D.A. / Ettmayer, P. / Gerstberger, T. / Kofink, C. / Wunberg, T. / Zoephel, A. / Fu, S.C. / Teh, J.L. / Bottcher, J. / Pototschnig, N. / Schachinger, F. / Schipany, K. / Lieb, S. / Vellano, C.P. / O'Connell, J.C. / Mendes, R.L. / Moll, J. / Petronczki, M. / Heffernan, T.P. / Pearson, M. / McConnell, D.B. / Kraut, N.
History
DepositionJul 24, 2019Deposition site: PDBE / Processing site: PDBE
Revision 1.0Aug 26, 2020Provider: repository / Type: Initial release
Revision 1.1Mar 10, 2021Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Jun 2, 2021Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.year
Revision 1.3May 15, 2024Group: Data collection / Database references / Category: chem_comp_atom / chem_comp_bond / database_2
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)58,0149
Polymers57,1031
Non-polymers9118
Water6,846380
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1490 Å2
ΔGint25 kcal/mol
Surface area24360 Å2
MethodPISA
Unit cell
Length a, b, c (Å)38.007, 78.74, 168.924
Angle α, β, γ (deg.)90, 90, 90
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 (E. coli) / References: UniProt: Q07889
#2: Chemical ChemComp-IMD / IMIDAZOLE


Mass: 69.085 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C3H5N2
#3: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: C2H6O2
#4: Chemical ChemComp-L7H / ~{N}-[(1~{R})-1-[3-azanyl-5-(trifluoromethyl)phenyl]ethyl]-7-methoxy-2-methyl-6-[(3~{S})-oxolan-3-yl]oxy-quinazolin-4-amine


Mass: 462.465 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Formula: C23H25F3N4O3 / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 380 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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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: 2.21 Å3/Da / Density % sol: 44.43 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 8 / Details: 13% PEG8000, 0.1M Imidazole pH=8.0

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06SA / Wavelength: 1 Å
DetectorType: DECTRIS EIGER X 4M / Detector: PIXEL / Date: Aug 8, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.866→84.462 Å / Num. obs: 34879 / % possible obs: 80.6 % / Redundancy: 9.6 % / CC1/2: 0.998 / Rmerge(I) obs: 0.132 / Rpim(I) all: 0.044 / Net I/σ(I): 12
Reflection shellResolution: 1.866→1.981 Å / Num. unique obs: 1744 / CC1/2: 0.342 / Rpim(I) all: 0.694

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Processing

Software
NameVersionClassification
BUSTER2.11.7refinement
XDSdata reduction
STARANISOdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.866→84.46 Å / Cor.coef. Fo:Fc: 0.941 / Cor.coef. Fo:Fc free: 0.928 / SU R Cruickshank DPI: 0.65 / Cross valid method: THROUGHOUT / SU R Blow DPI: 0.217 / SU Rfree Blow DPI: 0.16 / SU Rfree Cruickshank DPI: 0.156
RfactorNum. reflection% reflectionSelection details
Rfree0.22 1717 -RANDOM
Rwork0.199 ---
obs0.2 34893 77.4 %-
Displacement parametersBiso mean: 32.1 Å2
Baniso -1Baniso -2Baniso -3
1--1.6611 Å20 Å20 Å2
2--0.9988 Å20 Å2
3---0.6624 Å2
Refine analyzeLuzzati coordinate error obs: 0.27 Å
Refinement stepCycle: LAST / Resolution: 1.866→84.46 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3875 0 63 380 4318
LS refinement shellResolution: 1.84→1.94 Å
RfactorNum. reflection% reflection
Rfree0.2177 42 -
Rwork0.2372 --
obs0.2361 698 11.06 %
Refinement TLS params.Origin x: 8.7326 Å / Origin y: -15.3206 Å / Origin z: -22.1583 Å
111213212223313233
T0 Å20 Å20 Å2-0 Å20 Å2--0 Å2
L0 °20 °20 °2-0 °20 °2--0 °2
S0 Å °0 Å °0 Å °0 Å °0 Å °0 Å °0 Å °0 Å °0 Å °
Refinement TLS groupSelection details: { A|* }

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