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

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Basic information

Entry
Database: PDB / ID: 7zlr
TitleCrystal structure of SOCS2:ElonginB:ElonginC in complex with compound 13
Components
  • Elongin-B
  • Elongin-C
  • Suppressor of cytokine signaling 2
KeywordsLIGASE / E3 ligase / suppressor of cytokine signaling
Function / homology
Function and homology information


JAK pathway signal transduction adaptor activity / 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 ...JAK pathway signal transduction adaptor activity / 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 / cell surface receptor signaling pathway via JAK-STAT / Pausing and recovery of Tat-mediated HIV elongation / Tat-mediated HIV elongation arrest and recovery / phosphatidylinositol phosphate biosynthetic process / HIV elongation arrest and recovery / Pausing and recovery of HIV elongation / regulation of signal transduction / 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 / RNA Polymerase II Transcription Elongation / Formation of RNA Pol II elongation complex / Growth hormone receptor signaling / cellular response to hormone stimulus / RNA Polymerase II Pre-transcription Events / Negative regulation of FLT3 / lactation / positive regulation of neuron differentiation / Interleukin-7 signaling / transcription corepressor binding / transcription elongation by RNA polymerase II / regulation of cell growth / TP53 Regulates Transcription of DNA Repair Genes / transcription initiation at RNA polymerase II promoter / Vif-mediated degradation of APOBEC3G / insulin-like growth factor receptor binding / Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha / Inactivation of CSF3 (G-CSF) signaling / 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 / protein-macromolecule adaptor activity / Neddylation / ubiquitin-dependent protein catabolic process / protein-containing complex assembly / protein ubiquitination / intracellular signal transduction / ubiquitin protein ligase binding / regulation of transcription by RNA polymerase II / negative regulation of apoptotic process / nucleoplasm / cytoplasm / cytosol
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-JH9 / Suppressor of cytokine signaling 2 / Elongin-C / Elongin-B
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.01 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

Downloads & links

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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)43,9404
Polymers43,3963
Non-polymers5441
Water2,144119
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4620 Å2
ΔGint-42 kcal/mol
Surface area17220 Å2
MethodPISA
Unit cell
Length a, b, c (Å)56.112, 52.246, 77.458
Angle α, β, γ (deg.)90.000, 108.269, 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-JH9 / [4-[(2~{S})-3-[(4-fluoranyl-3-prop-2-enyl-phenyl)methylamino]-2-[2-(4-fluorophenyl)ethanoylamino]-3-oxidanylidene-propyl]phenyl] dihydrogen phosphate


Mass: 544.484 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C27H27F2N2O6P / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 119 / 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: 2.48 Å3/Da / Density % sol: 50.49 %
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: I03 / Wavelength: 0.9763 Å
DetectorType: DECTRIS EIGER2 XE 16M / Detector: PIXEL / Date: May 19, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9763 Å / Relative weight: 1
ReflectionResolution: 2.007→53.284 Å / Num. obs: 24931 / % possible obs: 86.9 % / Redundancy: 6.5 % / Biso Wilson estimate: 32.22 Å2 / CC1/2: 0.989 / Rmerge(I) obs: 0.202 / Net I/σ(I): 7.3
Reflection shellResolution: 2.007→2.042 Å / Mean I/σ(I) obs: 1 / Num. unique obs: 1306 / CC1/2: 0.316

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Processing

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

Resolution: 2.01→53.28 Å / SU ML: 0.2893 / Cross valid method: FREE R-VALUE / σ(F): 1.33 / Phase error: 30.5437
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2554 1194 4.85 %
Rwork0.2 23421 -
obs0.2028 24615 85.77 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 42.96 Å2
Refinement stepCycle: LAST / Resolution: 2.01→53.28 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2822 0 38 119 2979
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00722922
X-RAY DIFFRACTIONf_angle_d0.91763958
X-RAY DIFFRACTIONf_chiral_restr0.0492446
X-RAY DIFFRACTIONf_plane_restr0.007501
X-RAY DIFFRACTIONf_dihedral_angle_d9.675400
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.01-2.090.4056540.31941218X-RAY DIFFRACTION40.47
2.09-2.180.3391140.27492875X-RAY DIFFRACTION94.47
2.18-2.30.3349900.26092053X-RAY DIFFRACTION68.18
2.3-2.440.28841590.2412921X-RAY DIFFRACTION96.52
2.44-2.630.25891610.24592951X-RAY DIFFRACTION97.68
2.63-2.90.30741170.2372395X-RAY DIFFRACTION78.87
2.9-3.310.29381770.20962941X-RAY DIFFRACTION97.87
3.31-4.170.2171500.16812994X-RAY DIFFRACTION98.22
4.18-53.280.21851720.1633073X-RAY DIFFRACTION98.42
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)
14.234301659780.184288712210.2268701703914.05132942774-1.178804324754.28146569840.06469846468470.0556235526791-0.1013658886450.0414391831682-0.195789368073-0.2927329985150.05349068230480.1396672861260.123593054170.1599566448340.0185509479595-0.03428875694240.108193897840.004457304338390.19707358751412.372614044-4.1533957259328.5400673897
24.170790253121.783023070831.203098402685.317688965091.127257361844.542650235810.0129937588481-0.4040708716310.04499732138730.310004021384-0.0484295436579-0.128893520625-0.11783038641-0.1724778890960.04338079421820.2076385139290.002154117767520.008197042754880.130208749641-0.02688211818280.1887517222318.361564336165.1469367035536.5181630843
33.108508268511.3481706669-0.3393980421422.96979850359-0.3603117342611.933117436270.134296441353-0.2138930927060.161779680080.380532498791-0.2149280702410.153812110802-0.0631270661275-0.2147244588640.07095497264840.243275631336-0.0253986081115-0.02524386382740.243918314425-0.06844800578590.221423449641-4.21792411889-2.3788493751330.8083790338
42.72882019158-1.52953765532-3.182514780831.934854069220.1844026504796.56636894911-0.0691760285505-0.2773329050430.221000991302-0.286619967017-0.1014184820470.2301680954330.0806417774599-0.1334392501720.1696657218840.438372145666-0.14525245952-0.03381536831820.501274447699-0.1181385926330.30272591783-15.3612097286-17.91254777230.972674839976
52.440085280380.0756974141499-1.986290592520.8794725345210.4808966231734.0142839485-0.04558976768170.3811176221130.104798780393-0.2422151338090.1998978277720.06180798912170.0467337609415-0.43453365136-0.1558055508080.448667983514-0.0500618524125-0.03402315535160.469952378761-0.03771639913240.289406923472-21.2802144823-11.96606559062.79873542071
67.02242810856-0.3838180499170.2588247271063.277021711121.942064536826.322993605-0.2226088142670.91460639869-0.896394977653-0.0877619055150.04241450274890.1559193446380.820025350153-0.1167935269560.1772005017950.406927784702-0.1035936904310.01315402664180.343670542141-0.09075254025610.350850054572-16.0906136547-26.285842879115.9659160346
74.815932119411.660959390780.5734276408024.735406717930.5636068218134.17344385020.03785921288310.274756870023-0.0137406592147-0.05396351814850.07631025413940.01475343702940.184632844088-0.071625902617-0.07814595400770.242955950083-0.0435643896368-0.006880703359020.239616169-0.05803843542440.193703886538-11.6294097847-14.075422760920.4747721244
Refinement TLS group

Refine-ID: X-RAY DIFFRACTION

IDRefine TLS-IDSelection detailsAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
11chain 'A' and (resid 30 through 100 )AA30 - 1001 - 71
22chain 'A' and (resid 101 through 134 )AA101 - 13472 - 105
33chain 'A' and (resid 135 through 198 )AA135 - 198106 - 169
44chain 'B' and (resid 1 through 35 )BB1 - 351 - 35
55chain 'B' and (resid 36 through 104 )BB36 - 10436 - 104
66chain 'C' and (resid 17 through 61 )CC17 - 611 - 37
77chain 'C' and (resid 62 through 112 )CC62 - 11238 - 88

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