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- PDB-7avs: Crystal structure of SOS1 in complex with compound 6 -

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Basic information

Entry
Database: PDB / ID: 7avs
TitleCrystal structure of SOS1 in complex with compound 6
ComponentsSon of sevenless homolog 1
KeywordsPROTEIN BINDING / RasGEF
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 / positive regulation of epidermal growth factor receptor signaling pathway / epidermal growth factor receptor binding / Regulation of KIT signaling / NRAGE signals death through JNK / leukocyte migration / regulation of T cell proliferation / roof of mouth development / eyelid development in camera-type eye / B cell homeostasis / Fc-epsilon receptor signaling pathway / GRB2:SOS provides linkage to MAPK signaling for Integrins / neurotrophin TRK receptor signaling pathway / 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 / Signalling to RAS / SHC-related events triggered by IGF1R / Activated NTRK2 signals through FRS2 and FRS3 / Role of LAT2/NTAL/LAB on calcium mobilization / Interleukin receptor SHC signaling / Signal attenuation / SHC-mediated cascade:FGFR2 / SHC-mediated cascade:FGFR3 / MET activates RAS signaling / Signaling by PDGFRA transmembrane, juxtamembrane and kinase domain mutants / Signaling by PDGFRA extracellular domain mutants / Schwann cell development / SHC-mediated cascade:FGFR4 / Signaling by FGFR4 in disease / Erythropoietin activates RAS / SHC-mediated cascade:FGFR1 / FRS-mediated FGFR2 signaling / FRS-mediated FGFR3 signaling / Signaling by FLT3 ITD and TKD mutants / Signaling by FGFR2 in disease / FRS-mediated FGFR4 signaling / Signaling by FGFR3 in disease / Tie2 Signaling / FRS-mediated FGFR1 signaling / GRB2 events in EGFR signaling / FLT3 Signaling / SHC1 events in EGFR signaling / EGFR Transactivation by Gastrin / Signaling by FLT3 fusion proteins / RAC1 GTPase cycle / Signaling by FGFR1 in disease / myelination / GRB2 events in ERBB2 signaling / NCAM signaling for neurite out-growth / SHC1 events in ERBB2 signaling / Downstream signal transduction / Constitutive Signaling by Overexpressed ERBB2 / Insulin receptor signalling cascade / GTPase activator activity / FCERI mediated Ca+2 mobilization / insulin-like growth factor receptor signaling pathway / T cell activation / Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants / Antigen activates B Cell Receptor (BCR) leading to generation of second messengers / guanyl-nucleotide exchange factor activity / axon guidance / response to ischemia / molecular condensate scaffold activity / FCERI mediated MAPK activation / 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 / insulin receptor signaling pathway / 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 / Chem-S3Q / Son of sevenless homolog 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.28 Å
AuthorsBader, G. / Kessler, D. / Wolkerstorfer, B.
Funding support Austria, 1items
OrganizationGrant numberCountry
Austrian Research Promotion Agency854341, 861507, 867897 and 874517 Austria
CitationJournal: J.Med.Chem. / Year: 2021
Title: One Atom Makes All the Difference: Getting a Foot in the Door between SOS1 and KRAS.
Authors: Ramharter, J. / Kessler, D. / Ettmayer, P. / Hofmann, M.H. / Gerstberger, T. / Gmachl, M. / Wunberg, T. / Kofink, C. / Sanderson, M. / Arnhof, H. / Bader, G. / Rumpel, K. / Zophel, A. / ...Authors: Ramharter, J. / Kessler, D. / Ettmayer, P. / Hofmann, M.H. / Gerstberger, T. / Gmachl, M. / Wunberg, T. / Kofink, C. / Sanderson, M. / Arnhof, H. / Bader, G. / Rumpel, K. / Zophel, A. / Schnitzer, R. / Bottcher, J. / O'Connell, J.C. / Mendes, R.L. / Richard, D. / Pototschnig, N. / Weiner, I. / Hela, W. / Hauer, K. / Haering, D. / Lamarre, L. / Wolkerstorfer, B. / Salamon, C. / Werni, P. / Munico-Martinez, S. / Meyer, R. / Kennedy, M.D. / Kraut, N. / McConnell, D.B.
History
DepositionNov 6, 2020Deposition site: PDBE / Processing site: PDBE
Revision 1.0Mar 24, 2021Provider: repository / Type: Initial release
Revision 1.1Jun 9, 2021Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
Revision 1.2Jan 31, 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 / refine_hist
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _refine_hist.d_res_high

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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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)115,2668
Polymers114,2072
Non-polymers1,0596
Water9,764542
1
A: Son of sevenless homolog 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)57,6334
Polymers57,1031
Non-polymers5303
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Son of sevenless homolog 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)57,6334
Polymers57,1031
Non-polymers5303
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)83.932, 39.031, 174.752
Angle α, β, γ (deg.)90, 90.06, 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 / Production host: Escherichia coli (E. coli) / References: UniProt: Q07889
#2: Chemical
ChemComp-IMD / IMIDAZOLE


Mass: 69.085 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C3H5N2
#3: Chemical ChemComp-S3Q / 6,7-dimethoxy-2-methyl-~{N}-[(1~{R})-1-[3-(trifluoromethyl)phenyl]ethyl]quinazolin-4-amine


Mass: 391.387 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C20H20F3N3O2 / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 542 / 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: 2.51 Å3/Da / Density % sol: 50.92 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / Details: 6-11 % PEG 8000, 2 mM DTT, 60 mM Tris / PH range: 7.5-7.9

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X10SA / Wavelength: 0.99992 Å
DetectorType: DECTRIS PILATUS 6M-F / Detector: PIXEL / Date: Sep 7, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.99992 Å / Relative weight: 1
ReflectionResolution: 2.28→83.932 Å / Num. obs: 40777 / % possible obs: 77.2 % / Redundancy: 3.3 % / Rmerge(I) obs: 0.112 / Rsym value: 0.112 / Net I/σ(I): 8
Reflection shellResolution: 2.279→2.485 Å / Redundancy: 3.2 % / Rmerge(I) obs: 0.818 / Mean I/σ(I) obs: 1.3 / Num. unique obs: 816 / Rsym value: 0.818 / % possible all: 17.1

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Processing

Software
NameVersionClassification
BUSTER2.11.7refinement
autoPROCdata reduction
XDSJan 26, 201data reduction
autoPROC1.1.7data scaling
Aimlessdata scaling
STARANISOdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 7AVI

7avi


Resolution: 2.28→38.77 Å / Cor.coef. Fo:Fc: 0.92 / Cor.coef. Fo:Fc free: 0.881 / Cross valid method: THROUGHOUT / SU R Blow DPI: 0.623 / SU Rfree Blow DPI: 0.293
RfactorNum. reflection% reflectionSelection details
Rfree0.2594 1240 -RANDOM
Rwork0.2059 ---
obs0.2075 40769 76.4 %-
Displacement parametersBiso mean: 41.69 Å2
Baniso -1Baniso -2Baniso -3
1--0.9496 Å20 Å2-0.8552 Å2
2--5.0555 Å20 Å2
3----4.1059 Å2
Refine analyzeLuzzati coordinate error obs: 0.34 Å
Refinement stepCycle: LAST / Resolution: 2.28→38.77 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7710 0 76 545 8331
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.00815841HARMONIC2
X-RAY DIFFRACTIONt_angle_deg0.8728727HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d4674SINUSOIDAL2
X-RAY DIFFRACTIONt_gen_planes2454HARMONIC5
X-RAY DIFFRACTIONt_it8002HARMONIC10
X-RAY DIFFRACTIONt_chiral_improper_torsion1025SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies3HARMONIC1
X-RAY DIFFRACTIONt_ideal_dist_contact12444SEMIHARMONIC4
X-RAY DIFFRACTIONt_omega_torsion2.73
X-RAY DIFFRACTIONt_other_torsion15.46
LS refinement shellResolution: 2.28→2.41 Å
RfactorNum. reflection% reflection
Rfree0.3158 19 -
Rwork0.228 --
obs--9.21 %
Refinement TLS params.

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)
12.4991-0.23721.20690.1293-0.18770.63110.04960.00680.03880.0068-0.0051-0.00610.0388-0.0061-0.0444-0.067-0.0051-0.00680.0195-0.0042-0.1184-35.5111-5.7628-22.5486
22.75910.2852-1.36870.1662-0.21050.70070.0413-0.015-0.0395-0.0150.0067-0.0234-0.0395-0.0234-0.048-0.06420.0054-0.01590.01880.0051-0.12756.21056.4741-64.7599
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{ A|* }A563 - 1042
2X-RAY DIFFRACTION2{ B|* }B565 - 1042

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