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- PDB-8uc9: SOS2 co-crystal structure with fragment bound (compound 9) -

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Basic information

Entry
Database: PDB / ID: 8uc9
TitleSOS2 co-crystal structure with fragment bound (compound 9)
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 / Interleukin-15 signaling / positive regulation of small GTPase mediated signal transduction / Activation of RAC1 / NRAGE signals death through JNK / regulation of T cell proliferation / B cell homeostasis / RAC1 GTPase cycle / guanyl-nucleotide exchange factor activity ...regulation of pro-B cell differentiation / regulation of T cell differentiation in thymus / Interleukin-15 signaling / positive regulation of small GTPase mediated signal transduction / Activation of RAC1 / NRAGE signals death through JNK / regulation of T cell proliferation / 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-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
7-chloroquinolin-4-amine / Son of sevenless homolog 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.44 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
DepositionSep 26, 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

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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)57,5492
Polymers57,3711
Non-polymers1791
Water43224
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)51.762, 51.762, 206.748
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number78
Space group name H-MP43
Space group name HallP4cw
Symmetry operation#1: x,y,z
#2: -y,x,z+3/4
#3: y,-x,z+1/4
#4: -x,-y,z+1/2

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Components

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


Mass: 57370.676 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-QBC / 7-chloroquinolin-4-amine


Mass: 178.618 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C9H7ClN2 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 24 / 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: 2.41 Å3/Da / Density % sol: 49.04 %
Crystal growTemperature: 281 K / Method: vapor diffusion, hanging drop / pH: 7.5
Details: 10% PEG 3350, 100 mM NaMalonate pH5.5, SOS2 8 mg/mL

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 24-ID-E / Wavelength: 0.9796 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Jul 14, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9796 Å / Relative weight: 1
ReflectionResolution: 2.44→50 Å / Num. obs: 19562 / % possible obs: 96.6 % / Redundancy: 2.5 % / Biso Wilson estimate: 59.44 Å2 / CC1/2: 0.99 / Net I/σ(I): 14.9
Reflection shellResolution: 2.44→2.48 Å / Num. unique obs: 940 / CC1/2: 0.37

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Processing

Software
NameVersionClassification
PHENIX1.20.1_4487refinement
HKL-2000data reduction
HKL-2000data scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.44→46.28 Å / SU ML: 0.418 / Cross valid method: FREE R-VALUE / σ(F): 1.37 / Phase error: 33.8234
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2607 995 5.09 %
Rwork0.2141 18552 -
obs0.2166 19547 96.78 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 75.36 Å2
Refinement stepCycle: LAST / Resolution: 2.44→46.28 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3661 0 12 24 3697
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00153760
X-RAY DIFFRACTIONf_angle_d0.42365103
X-RAY DIFFRACTIONf_chiral_restr0.0364572
X-RAY DIFFRACTIONf_plane_restr0.0052658
X-RAY DIFFRACTIONf_dihedral_angle_d11.73151395
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.44-2.570.36181160.33052641X-RAY DIFFRACTION96.13
2.57-2.730.36571360.28292700X-RAY DIFFRACTION97.69
2.73-2.940.36891330.29932627X-RAY DIFFRACTION96.88
2.94-3.230.31771350.25022735X-RAY DIFFRACTION98.46
3.23-3.70.2641830.23552633X-RAY DIFFRACTION98.22
3.7-4.660.24011330.17912613X-RAY DIFFRACTION95.05
4.66-46.280.21321590.17792603X-RAY DIFFRACTION95.08
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)
13.981699118150.4282115738142.108861538573.357156334180.3603811162922.407969765780.110711867149-0.165765658044-0.5655465865220.509567395881-0.05963543160160.2622759602740.167400432469-0.794764232561-0.04534243978430.428815403058-0.03664985443810.102464938410.616842368936-0.02849875758840.481524525308-14.5580529668-23.7300959554-29.275412766
24.990009641251.200551355372.10133629023.37723864102-0.06252246584213.26877018093-0.444811238033-0.531378048925-0.3483339258290.3218423937720.1265666502030.372284761398-0.216067259444-0.6131789065150.298019080360.4249584918790.03789131814830.1225895954650.550151195193-0.1325370518510.520099391876-17.3265928807-13.3469989882-32.4681239982
31.11738310050.8840999397691.258789682793.775976100743.653377189265.44750741678-0.351672268215-0.1147009535440.425720799871-0.559859293643-0.2014179624190.807820770764-0.894410288827-0.7381132220940.5546545374530.586566691870.175375560719-0.05693811162980.5488747488690.05137554006370.575388301882-8.84862411836-0.277619198371-30.6709163046
44.728245195871.405133738432.773520356791.537176081850.6364733454882.943072033740.02555419424980.133856681386-0.245293677371-0.04460483899920.206209734293-0.0563548871408-0.173151091855-0.0464490372596-0.2418569423410.4024831995370.06686079282220.07840031388130.383319239424-0.01493215944590.35662855790219.63055029660.679322283974-4.73748688444
53.205295315842.210005351112.949825269531.572847388862.399171783714.252220848350.598291772432-0.48506256192-0.5286017665790.6242406542770.200011431239-0.7180395694281.3409865387-0.446478301374-0.8068129902640.7952639805110.0441034098449-0.1244446047980.7047843637520.03235691760370.7934465027854.72062221923-19.1640998492-9.26218382617
62.074652347211.616153006021.721247975231.942745295942.194279825232.495479215860.0266601621179-0.04995575741290.0952598744818-0.115978725388-0.0671352502540.1837049811260.1889631610580.07362386130490.03275537047830.5217341855140.1792855191290.01139386255920.5867438582370.1398498317090.4718018425338.50517471037-2.58746196988-12.8548896509
75.07979319235-0.8825664403490.1347806114144.360044397451.42441735894.13864899520.1239608063720.358473236976-0.296014705879-0.191914293590.107601836982-0.310908315826-0.2095112154790.320221609541-0.2264796791560.398176670530.01303029951670.04218178983070.424664300449-0.009508426159220.38633470978336.22307288171.40180674288-1.40587052732
Refinement TLS group

Refine-ID: X-RAY DIFFRACTION / Auth asym-ID: A / Label asym-ID: A

IDRefine TLS-IDSelection detailsAuth seq-IDLabel seq-ID
11chain 'A' and (resid 564 through 663 )564 - 6631 - 85
22chain 'A' and (resid 664 through 705 )664 - 70586 - 127
33chain 'A' and (resid 706 through 757 )706 - 757128 - 176
44chain 'A' and (resid 758 through 905 )758 - 905177 - 324
55chain 'A' and (resid 906 through 955 )906 - 955325 - 372
66chain 'A' and (resid 956 through 999 )956 - 999373 - 416
77chain 'A' and (resid 1000 through 1040 )1000 - 1040417 - 457

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