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- PDB-6sfr: SOS1 in Complex with Inhibitor BI-68BS -

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Basic information

Entry
Database: PDB / ID: 6sfr
TitleSOS1 in Complex with Inhibitor BI-68BS
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 / 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 / epidermal growth factor receptor binding / Regulation of KIT signaling / 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 / RET signaling / Activated NTRK3 signals through RAS / 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 / EGFR Transactivation by Gastrin / Signaling by FLT3 fusion proteins / FLT3 Signaling / myelination / Signaling by FGFR1 in disease / GRB2 events in ERBB2 signaling / NCAM signaling for neurite out-growth / SHC1 events in ERBB2 signaling / Downstream signal transduction / FCERI mediated Ca+2 mobilization / Constitutive Signaling by Overexpressed ERBB2 / Insulin receptor signalling cascade / GTPase activator activity / 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 / molecular condensate scaffold activity / response to ischemia / FCERI mediated MAPK activation / axon guidance / B cell receptor signaling pathway / Signaling by ERBB2 TMD/JMD mutants / Constitutive Signaling by EGFRvIII / Signaling by ERBB2 ECD mutants / epidermal growth factor receptor signaling pathway / Signaling by ERBB2 KD Mutants / Signaling by SCF-KIT / multicellular organism growth / cytokine-mediated signaling pathway / SH3 domain binding / Signaling by CSF1 (M-CSF) in myeloid cells / G alpha (12/13) signalling events / DAP12 signaling / Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants / 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
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 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
Similarity search - Domain/homology
IMIDAZOLE / Chem-LBK / Son of sevenless homolog 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 1.917 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
DepositionAug 2, 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 1, 2024Group: Advisory / Data collection ...Advisory / 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 / pdbx_unobs_or_zero_occ_atoms
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
B: Son of sevenless homolog 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)115,1028
Polymers114,2072
Non-polymers8956
Water25,2031399
1
A: Son of sevenless homolog 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)57,5514
Polymers57,1031
Non-polymers4483
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Son of sevenless homolog 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)57,5514
Polymers57,1031
Non-polymers4483
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)84, 39.292, 176.494
Angle α, β, γ (deg.)90, 90.03, 90
Int Tables number4
Space group name H-MP1211

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Components

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


Mass: 57103.285 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SOS1 / Plasmid: pDEST17 / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: Q07889
#2: Chemical
ChemComp-IMD / IMIDAZOLE / Imidazole


Mass: 69.085 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C3H5N2
#3: Chemical ChemComp-LBK / 6,7-dimethoxy-~{N}-[(1~{R})-1-phenylethyl]quinazolin-4-amine


Mass: 309.362 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C18H19N3O2 / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 1399 / 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: 2.66 Å3/Da / Density % sol: 53.8 %
Crystal growTemperature: 277 K / Method: vapor diffusion / pH: 7.4 / Details: 0.1 M Imidazole, 3% PEG8000

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SEALED TUBE / Type: RIGAKU MICROMAX-003 / Wavelength: 1.5418 Å
DetectorType: RIGAKU / Detector: CCD / Date: Mar 11, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 1.917→84 Å / Num. obs: 74854 / % possible obs: 83.4 % / Redundancy: 2.8 % / CC1/2: 0.998 / Rmerge(I) obs: 0.052 / Rsym value: 0.052 / Net I/σ(I): 14
Reflection shellResolution: 1.917→2.028 Å / Redundancy: 1.5 % / Rmerge(I) obs: 0.433 / Mean I/σ(I) obs: 1.5 / Num. unique obs: 3744 / CC1/2: 0.653 / Rsym value: 0.433 / % possible all: 27.4

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Processing

Software
NameVersionClassification
BUSTER2.11.7refinement
XDSJan 26, 201data reduction
autoPROC1.1.7data scaling
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: inhouse

Resolution: 1.917→84 Å / Cor.coef. Fo:Fc: 0.924 / Cor.coef. Fo:Fc free: 0.883 / SU R Cruickshank DPI: 0.463 / Cross valid method: THROUGHOUT / SU R Blow DPI: 0.23 / SU Rfree Blow DPI: 0.185 / SU Rfree Cruickshank DPI: 0.174
RfactorNum. reflection% reflectionSelection details
Rfree0.245 2282 -RANDOM
Rwork0.198 ---
obs0.2 74929 82.7 %-
Displacement parametersBiso mean: 25.97 Å2
Baniso -1Baniso -2Baniso -3
1-0.3469 Å20 Å20.0018 Å2
2--0.3879 Å20 Å2
3----0.7348 Å2
Refine analyzeLuzzati coordinate error obs: 0.27 Å
Refinement stepCycle: LAST / Resolution: 1.917→84 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7710 0 66 1399 9175
LS refinement shellResolution: 1.91→1.98 Å
RfactorNum. reflection% reflection
Rfree0.3169 35 -
Rwork0.273 --
obs0.274 1499 17.62 %
Refinement TLS params.

L11: 0 °2 / L12: 0 °2 / L13: 0 °2 / L22: 0 °2 / L23: 0 °2 / L33: 0 °2 / S11: 0 Å ° / S12: 0 Å ° / S13: 0 Å ° / S21: 0 Å ° / S22: 0 Å ° / S23: 0 Å ° / S31: 0 Å ° / S32: 0 Å ° / S33: 0 Å ° / T11: 0 Å2 / T12: 0 Å2 / T13: 0 Å2 / T22: 0 Å2 / T23: 0 Å2 / T33: 0 Å2 / Refine-ID: X-RAY DIFFRACTION

IDOrigin x (Å)Origin y (Å)Origin z (Å)
1-35.60213.7848-22.6768
26.223426.0749-65.456
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1{ A|* }
2X-RAY DIFFRACTION2{ B|* }

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