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- PDB-8uh0: SOS2 co-crystal structure with fragment bound (compound 10) -

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Basic information

Entry
Database: PDB / ID: 8uh0
TitleSOS2 co-crystal structure with fragment bound (compound 10)
ComponentsSon of sevenless homolog 2
KeywordsSIGNALING PROTEIN / SOS2 / Nucleotide Exchange Factor / GEF / KRAS / RAS / Fragment screening / FBLD
Function / homology
Function and homology information


regulation of pro-B cell differentiation / regulation of T cell differentiation in thymus / positive regulation of small GTPase mediated signal transduction / Interleukin-15 signaling / Activation of RAC1 / regulation of T cell proliferation / NRAGE signals death through JNK / B cell homeostasis / RAC1 GTPase cycle / guanyl-nucleotide exchange factor activity ...regulation of pro-B cell differentiation / regulation of T cell differentiation in thymus / positive regulation of small GTPase mediated signal transduction / Interleukin-15 signaling / Activation of RAC1 / regulation of T cell proliferation / NRAGE signals death through JNK / B cell homeostasis / RAC1 GTPase cycle / guanyl-nucleotide exchange factor activity / G alpha (12/13) signalling events / insulin receptor signaling pathway / Ras protein signal transduction / protein heterodimerization activity / plasma membrane / cytosol
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
8-hydroxyquinoline-2-carbonitrile / Son of sevenless homolog 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.73 Å
AuthorsGunn, R.J. / Lawson, J.D.
Funding support United States, 1items
OrganizationGrant numberCountry
Not funded United States
CitationJournal: J.Med.Chem. / Year: 2024
Title: Discovery of Five SOS2 Fragment Hits with Binding Modes Determined by SOS2 X-Ray Cocrystallography.
Authors: Smith, C.R. / Chen, D. / Christensen, J.G. / Coulombe, R. / Fethiere, J. / Gunn, R.J. / Hollander, J. / Jones, B. / Ketcham, J.M. / Khare, S. / Kuehler, J. / Lawson, J.D. / Marx, M.A. / ...Authors: Smith, C.R. / Chen, D. / Christensen, J.G. / Coulombe, R. / Fethiere, J. / Gunn, R.J. / Hollander, J. / Jones, B. / Ketcham, J.M. / Khare, S. / Kuehler, J. / Lawson, J.D. / Marx, M.A. / Olson, P. / Pearson, K.E. / Ren, C. / Tsagris, D. / Ulaganathan, T. / Van't Veer, I. / Wang, X. / Ivetac, A.
History
DepositionOct 6, 2023Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 10, 2024Provider: repository / Type: Initial release
Revision 1.1Jan 24, 2024Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.year / _citation_author.identifier_ORCID
Revision 1.2Mar 13, 2024Group: Database references / Category: citation_author / Item: _citation_author.identifier_ORCID

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Son of sevenless homolog 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)56,9432
Polymers56,7731
Non-polymers1701
Water1,13563
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)52.616, 52.759, 61.103
Angle α, β, γ (deg.)84.95, 83.89, 67.40
Int Tables number1
Space group name H-MP1
Symmetry operation#1: x,y,z

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Components

#1: Protein Son of sevenless homolog 2 / SOS-2


Mass: 56773.039 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SOS2 / Production host: Escherichia coli (E. coli) / References: UniProt: Q07890
#2: Chemical ChemComp-WRN / 8-hydroxyquinoline-2-carbonitrile


Mass: 170.167 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C10H6N2O / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 63 / 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: 2.71 Å3/Da / Density % sol: 54.62 %
Crystal growTemperature: 281 K / Method: vapor diffusion, sitting drop / Details: 10% PEG 3350, 9 mM fragment

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 24-ID-E / Wavelength: 0.979 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Nov 19, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.979 Å / Relative weight: 1
ReflectionResolution: 2.73→50 Å / Num. obs: 9052 / % possible obs: 90.7 % / Redundancy: 2 % / Biso Wilson estimate: 39.81 Å2 / CC1/2: 0.98 / Net I/σ(I): 8.3
Reflection shellResolution: 2.73→2.91 Å / Num. unique obs: 2070 / CC1/2: 0.68

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Processing

Software
NameVersionClassification
PHENIX(1.20.1_4487)refinement
HKL-2000data reduction
HKL-2000data scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.73→48.64 Å / SU ML: 0.41 / Cross valid method: FREE R-VALUE / σ(F): 1.72 / Phase error: 28.72 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2694 443 4.9 %
Rwork0.2213 --
obs0.2238 9048 56.67 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.73→48.64 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3613 0 0 63 3676
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_dihedral_angle_d9.4611389
X-RAY DIFFRACTIONf_chiral_restr0.036556
X-RAY DIFFRACTIONf_plane_restr0.003644
LS refinement shellResolution: 3.94→10 Å
RfactorNum. reflection% reflection
Rfree0.2453 217 -
Rwork0.1985 3966 -
obs--79 %
Refinement TLS params.

Method: refined / 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)
10.0318-0.0282-0.01150.02180.00930.0041-0.0398-0.03390.07930.0159-0.01140.03340.0243-0.0551-0.03110.34570.34490.05490.4236-0.38110.448113.684651.171315.9293
20.00840.00930.00210.0086-0.00430.01230.08620.03870.13160.04750.1199-0.06920.0578-0.059300.40730.07390.06020.6735-0.05390.55485.034845.39697.4707
30.02110.0262-0.10720.0446-0.13730.64430.0695-0.3284-0.04960.08650.24510.0453-0.0281-0.23170.07750.14730.02550.030.5185-0.07710.33266.365837.100112.1718
40.326-0.11430.12240.0610.0090.17950.0743-0.255-0.0693-0.17770.0830.01290.2218-0.21280.05650.5484-0.0003-0.11490.2232-0.00460.248115.894234.85998.8595
50.58630.08530.24410.01410.01860.28110.2812-0.56240.03830.0517-0.00390.17380.1645-0.33720.07190.48790.0102-0.00230.3290.00830.244521.494231.285815.1476
60.0730.0456-0.01530.14590.03530.02690.0268-0.0258-0.14020.08560.01770.00190.3137-0.19570.010.8494-0.16870.01370.36980.02390.264323.476113.778815.9692
71.7464-0.11220.07840.2304-0.3272.0399-0.52640.6617-0.1162-0.0541-0.1113-0.253-0.55410.6545-1.76330.30020.0160.03020.28470.0315-0.047115.205-0.1776-12.6218
80.68480.1467-0.16530.27830.07350.4515-0.00910.3256-0.0445-0.185-0.03160.224-0.1017-0.07380.00980.13920.03-0.00220.15170.00170.23890.8042.6512-13.4954
90.21280.1475-0.10930.0876-0.0680.1421-0.22730.33410.2026-0.1292-0.2208-0.0959-0.0094-0.0079-1.0380.0668-0.0374-0.26730.30870.2190.374511.910313.9508-4.3616
100.3339-0.04320.21540.083-0.00520.1681-0.19470.5789-0.1345-0.4606-0.0738-0.1075-0.06290.2701-0.38990.4964-0.1730.17870.3888-0.12010.180311.4386-6.3767-29.4162
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'A' and (resid 565 through 573 )
2X-RAY DIFFRACTION2chain 'A' and (resid 574 through 586 )
3X-RAY DIFFRACTION3chain 'A' and (resid 596 through 618 )
4X-RAY DIFFRACTION4chain 'A' and (resid 619 through 652 )
5X-RAY DIFFRACTION5chain 'A' and (resid 672 through 722 )
6X-RAY DIFFRACTION6chain 'A' and (resid 723 through 757 )
7X-RAY DIFFRACTION7chain 'A' and (resid 758 through 862 )
8X-RAY DIFFRACTION8chain 'A' and (resid 863 through 941 )
9X-RAY DIFFRACTION9chain 'A' and (resid 942 through 999 )
10X-RAY DIFFRACTION10chain 'A' and (resid 1000 through 1041 )

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