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- PDB-8xjj: Co-crystal structure of SOS-1 and a potent, selective and orally ... -

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Basic information

Entry
Database: PDB / ID: 8xjj
TitleCo-crystal structure of SOS-1 and a potent, selective and orally bioavailable SOS1 inhibitor RGT-018
ComponentsSon of sevenless homolog 1
KeywordsSIGNALING PROTEIN / SOS1 / selective inhibitor / KRAS-driven cancers
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 / NRAGE signals death through JNK / Regulation of KIT signaling / positive regulation of epidermal growth factor receptor signaling pathway / epidermal growth factor receptor binding / 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 / hair follicle development / SHC1 events in ERBB4 signaling / 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 / GTPase activator activity / Downstream signal transduction / Constitutive Signaling by Overexpressed ERBB2 / FCERI mediated Ca+2 mobilization / Insulin receptor signalling cascade / Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants / guanyl-nucleotide exchange factor activity / insulin-like growth factor receptor signaling pathway / T cell activation / Antigen activates B Cell Receptor (BCR) leading to generation of second messengers / 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 / Signaling by SCF-KIT / epidermal growth factor receptor signaling pathway / Signaling by ERBB2 KD Mutants / 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 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 / 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
: / Son of sevenless homolog 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.1 Å
AuthorsRen, X.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Mol.Cancer Ther. / Year: 2024
Title: Discovery of RGT-018: a Potent, Selective and Orally Bioavailable SOS1 Inhibitor for KRAS-driven Cancers.
Authors: Xiao, F. / Wang, K. / Wang, X. / Li, H. / Hu, Z. / Ren, X. / Huang, W. / Feng, T. / Yao, L. / Lin, J. / Li, C. / Zhang, Z. / Mei, L. / Zhu, X. / Zhong, W. / Xie, Z.
History
DepositionDec 21, 2023Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Aug 14, 2024Provider: 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)69,26614
Polymers67,9851
Non-polymers1,28013
Water1,74797
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)40.760, 83.850, 179.020
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: 67985.281 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-A1LVJ / 5-[4-[[(1~{R})-1-[3-[bis(fluoranyl)methyl]-2-fluoranyl-phenyl]ethyl]amino]-2-methyl-6-morpholin-4-yl-7-oxidanylidene-pyrido[4,3-d]pyrimidin-8-yl]pyridine-2-carbonitrile


Mass: 535.520 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C27H24F3N7O2 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 12 / Source method: obtained synthetically / Formula: C2H6O2
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 97 / 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: 2.25 Å3/Da / Density % sol: 45.33 %
Crystal growTemperature: 295 K / Method: vapor diffusion, hanging drop / Details: 0.1 M imidazole 8.0, 6% PEG 8000

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I03 / Wavelength: 0.98 Å
DetectorType: DECTRIS EIGER2 XE 16M / Detector: PIXEL / Date: Dec 12, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.98 Å / Relative weight: 1
ReflectionResolution: 2.1→44.8 Å / Num. obs: 36854 / % possible obs: 99.95 % / Redundancy: 2 % / CC1/2: 1 / Net I/σ(I): 26.38
Reflection shellResolution: 2.1→2.175 Å / Num. unique obs: 3624 / CC1/2: 0.927

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Processing

Software
NameVersionClassification
REFMAC5.8.0258refinement
XDSdata reduction
Aimlessdata scaling
PHENIXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5OVE

5ove


Resolution: 2.1→44.8 Å / Cor.coef. Fo:Fc: 0.96 / Cor.coef. Fo:Fc free: 0.942 / SU B: 6.954 / SU ML: 0.173 / Cross valid method: THROUGHOUT / ESU R: 0.221 / ESU R Free: 0.193 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.26389 1855 5 %RANDOM
Rwork0.21976 ---
obs0.22202 34998 99.97 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 59.841 Å2
Baniso -1Baniso -2Baniso -3
1-5.68 Å2-0 Å20 Å2
2---4.69 Å2-0 Å2
3----0.98 Å2
Refinement stepCycle: 1 / Resolution: 2.1→44.8 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3920 0 87 97 4104
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0080.0134105
X-RAY DIFFRACTIONr_bond_other_d0.0010.0173877
X-RAY DIFFRACTIONr_angle_refined_deg1.5581.6775528
X-RAY DIFFRACTIONr_angle_other_deg1.2641.5799014
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.7595473
X-RAY DIFFRACTIONr_dihedral_angle_2_deg33.35121.915235
X-RAY DIFFRACTIONr_dihedral_angle_3_deg17.27315745
X-RAY DIFFRACTIONr_dihedral_angle_4_deg20.8431533
X-RAY DIFFRACTIONr_chiral_restr0.0750.2522
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.024442
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02857
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_it5.1036.1641895
X-RAY DIFFRACTIONr_mcbond_other5.0916.1621894
X-RAY DIFFRACTIONr_mcangle_it6.8999.2172364
X-RAY DIFFRACTIONr_mcangle_other6.9049.222365
X-RAY DIFFRACTIONr_scbond_it5.2716.5572210
X-RAY DIFFRACTIONr_scbond_other5.276.5572211
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other7.3469.6243164
X-RAY DIFFRACTIONr_long_range_B_refined9.44570.3444691
X-RAY DIFFRACTIONr_long_range_B_other9.44670.3314687
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.1→2.155 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.402 132 -
Rwork0.36 2584 -
obs--100 %

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