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- PDB-7zln: Crystal structure of SOCS2:ElonginB:ElonginC in complex with comp... -

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Basic information

Entry
Database: PDB / ID: 7zln
TitleCrystal structure of SOCS2:ElonginB:ElonginC in complex with compound 11
Components
  • Elongin-B
  • Elongin-C
  • Suppressor of cytokine signaling 2
KeywordsLIGASE / E3 ligase / suppressor of cytokine signaling
Function / homology
Function and homology information


negative regulation of growth hormone receptor signaling pathway / JAK pathway signal transduction adaptor activity / phosphorylation-dependent protein binding / negative regulation of receptor signaling pathway via JAK-STAT / 1-phosphatidylinositol-3-kinase regulator activity / target-directed miRNA degradation / elongin complex / VCB complex / phosphatidylinositol 3-kinase complex / growth hormone receptor binding ...negative regulation of growth hormone receptor signaling pathway / JAK pathway signal transduction adaptor activity / phosphorylation-dependent protein binding / negative regulation of receptor signaling pathway via JAK-STAT / 1-phosphatidylinositol-3-kinase regulator activity / target-directed miRNA degradation / elongin complex / VCB complex / phosphatidylinositol 3-kinase complex / growth hormone receptor binding / Cul5-RING ubiquitin ligase complex / growth hormone receptor signaling pathway / Cul2-RING ubiquitin ligase complex / negative regulation of multicellular organism growth / Pausing and recovery of Tat-mediated HIV elongation / Tat-mediated HIV elongation arrest and recovery / phosphatidylinositol phosphate biosynthetic process / cell surface receptor signaling pathway via JAK-STAT / HIV elongation arrest and recovery / Pausing and recovery of HIV elongation / regulation of signal transduction / ubiquitin-like ligase-substrate adaptor activity / Tat-mediated elongation of the HIV-1 transcript / mammary gland alveolus development / Formation of HIV-1 elongation complex containing HIV-1 Tat / Formation of HIV elongation complex in the absence of HIV Tat / negative regulation of signal transduction / RNA Polymerase II Transcription Elongation / Formation of RNA Pol II elongation complex / Growth hormone receptor signaling / cellular response to hormone stimulus / insulin-like growth factor receptor binding / RNA Polymerase II Pre-transcription Events / Negative regulation of FLT3 / lactation / positive regulation of neuron differentiation / Interleukin-7 signaling / transcription corepressor binding / regulation of cell growth / TP53 Regulates Transcription of DNA Repair Genes / transcription initiation at RNA polymerase II promoter / transcription elongation by RNA polymerase II / Vif-mediated degradation of APOBEC3G / Inactivation of CSF3 (G-CSF) signaling / Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha / Evasion by RSV of host interferon responses / Regulation of expression of SLITs and ROBOs / Antigen processing: Ubiquitination & Proteasome degradation / positive regulation of proteasomal ubiquitin-dependent protein catabolic process / response to estradiol / Neddylation / protein-macromolecule adaptor activity / ubiquitin-dependent protein catabolic process / protein-containing complex assembly / proteasome-mediated ubiquitin-dependent protein catabolic process / intracellular signal transduction / protein ubiquitination / ubiquitin protein ligase binding / negative regulation of apoptotic process / regulation of transcription by RNA polymerase II / nucleoplasm / cytosol / cytoplasm
Similarity search - Function
Suppressor of cytokine signalling 2 / SOCS2, SH2 domain / suppressors of cytokine signalling / SOCS box / SOCS box-like domain superfamily / SOCS box domain / SOCS box domain profile. / SOCS_box / Elongin B / Elongin-C ...Suppressor of cytokine signalling 2 / SOCS2, SH2 domain / suppressors of cytokine signalling / SOCS box / SOCS box-like domain superfamily / SOCS box domain / SOCS box domain profile. / SOCS_box / Elongin B / Elongin-C / S-phase kinase-associated protein 1-like / SKP1 component, POZ domain / Skp1 family, tetramerisation domain / Found in Skp1 protein family / SKP1/BTB/POZ domain superfamily / SH2 domain / Src homology 2 (SH2) domain profile. / Src homology 2 domains / SH2 domain / SH2 domain superfamily / Ubiquitin family / Ubiquitin homologues / Ubiquitin domain profile. / Ubiquitin-like domain / Ubiquitin-like domain superfamily
Similarity search - Domain/homology
Chem-JI9 / Suppressor of cytokine signaling 2 / Elongin-C / Elongin-B
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.6 Å
AuthorsRamachandran, S. / Ciulli, A. / Makukhin, N.
Funding supportEuropean Union, Switzerland, 2items
OrganizationGrant numberCountry
European Research Council (ERC)ERC-2012-StG-311460 DrugE3CRLsEuropean Union
Innovative Medicines Initiative875510 Switzerland
CitationJournal: Nat Commun / Year: 2023
Title: Structure-based design of a phosphotyrosine-masked covalent ligand targeting the E3 ligase SOCS2.
Authors: Ramachandran, S. / Makukhin, N. / Haubrich, K. / Nagala, M. / Forrester, B. / Lynch, D.M. / Casement, R. / Testa, A. / Bruno, E. / Gitto, R. / Ciulli, A.
History
DepositionApr 15, 2022Deposition site: PDBE / Processing site: PDBE
Revision 1.0Apr 26, 2023Provider: repository / Type: Initial release
Revision 1.1Oct 11, 2023Group: Data collection / Database references / Category: chem_comp_atom / chem_comp_bond / citation / Item: _citation.pdbx_database_id_DOI / _citation.year
Revision 1.2Oct 25, 2023Group: 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.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.3May 1, 2024Group: Refinement description / Category: pdbx_initial_refinement_model

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Suppressor of cytokine signaling 2
B: Elongin-B
C: Elongin-C
hetero molecules


Theoretical massNumber of molelcules
Total (without water)43,9144
Polymers43,3963
Non-polymers5181
Water50428
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4300 Å2
ΔGint-42 kcal/mol
Surface area17990 Å2
MethodPISA
Unit cell
Length a, b, c (Å)56.687, 52.258, 77.491
Angle α, β, γ (deg.)90.000, 107.941, 90.000
Int Tables number4
Space group name H-MP1211
Space group name HallP2yb
Symmetry operation#1: x,y,z
#2: -x,y+1/2,-z

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Components

#1: Protein Suppressor of cytokine signaling 2 / SOCS-2 / Cytokine-inducible SH2 protein 2 / CIS-2 / STAT-induced STAT inhibitor 2 / SSI-2


Mass: 19273.268 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SOCS2, CIS2, SSI2, STATI2 / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: O14508
#2: Protein Elongin-B / EloB / Elongin 18 kDa subunit / RNA polymerase II transcription factor SIII subunit B / SIII p18 / ...EloB / Elongin 18 kDa subunit / RNA polymerase II transcription factor SIII subunit B / SIII p18 / Transcription elongation factor B polypeptide 2


Mass: 13147.781 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ELOB, TCEB2 / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: Q15370
#3: Protein Elongin-C / EloC / Elongin 15 kDa subunit / RNA polymerase II transcription factor SIII subunit C / SIII p15 / ...EloC / Elongin 15 kDa subunit / RNA polymerase II transcription factor SIII subunit C / SIII p15 / Transcription elongation factor B polypeptide 1


Mass: 10974.616 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ELOC, TCEB1 / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: Q15369
#4: Chemical ChemComp-JI9 / [4-[(2~{S})-3-[(4-fluoranyl-3-methyl-phenyl)methylamino]-2-[2-(4-fluorophenyl)ethanoylamino]-3-oxidanylidene-propyl]phenyl] dihydrogen phosphate


Mass: 518.446 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C25H25F2N2O6P / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 28 / 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: 2.52 Å3/Da / Density % sol: 51.12 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop
Details: 100mM Tris-bicine, PEG8K (9-14%), ethylene glycol (26-20%) with seeding
PH range: 6.5-7

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I04 / Wavelength: 0.9795 Å
DetectorType: DECTRIS EIGER2 X 16M / Detector: PIXEL / Date: Jan 31, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9795 Å / Relative weight: 1
ReflectionResolution: 2.6→54.01 Å / Num. obs: 13506 / % possible obs: 99.9 % / Redundancy: 3.7 % / Biso Wilson estimate: 61.01 Å2 / CC1/2: 0.103 / Rpim(I) all: 0.763 / Net I/σ(I): 2.9
Reflection shellResolution: 2.6→2.67 Å / Num. unique obs: 962 / CC1/2: 0.005

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Processing

Software
NameVersionClassification
Cootmodel building
PHENIX1.19.2_4158refinement
xia2data reduction
xia2data scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: SBC

Resolution: 2.6→53.93 Å / SU ML: 0.6534 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 45.8056
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.3338 674 5.28 %
Rwork0.2799 12087 -
obs0.2827 12761 94.33 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 66.05 Å2
Refinement stepCycle: LAST / Resolution: 2.6→53.93 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2618 0 36 28 2682
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00212713
X-RAY DIFFRACTIONf_angle_d0.55323700
X-RAY DIFFRACTIONf_chiral_restr0.0395425
X-RAY DIFFRACTIONf_plane_restr0.0049476
X-RAY DIFFRACTIONf_dihedral_angle_d6.7155385
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.6-2.80.45671240.44712042X-RAY DIFFRACTION81.74
2.8-3.080.38021110.38642371X-RAY DIFFRACTION91.89
3.08-3.520.38211480.31982534X-RAY DIFFRACTION99.48
3.52-4.440.36231590.27732500X-RAY DIFFRACTION98.3
4.44-53.930.25851320.22812640X-RAY DIFFRACTION99.89

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