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- PDB-7z0l: IL-27 signalling complex -

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Basic information

Entry
Database: PDB / ID: 7z0l
TitleIL-27 signalling complex
Components
  • Interleukin-27 receptor subunit alpha
  • Interleukin-27 subunit beta,Interleukin-27 subunit alpha
  • Interleukin-6 receptor subunit beta
KeywordsCYTOKINE / immunosuppression / EBI3 / IL-27R-alpha / gp130 / p28.
Function / homology
Function and homology information


interleukin-27 receptor binding / regulation of T-helper 1 cell differentiation / negative regulation of T cell extravasation / negative regulation of cellular extravasation / negative regulation of T-helper 17 type immune response / IL-6-type cytokine receptor ligand interactions / leukemia inhibitory factor receptor activity / oncostatin-M receptor activity / MAPK3 (ERK1) activation / MAPK1 (ERK2) activation ...interleukin-27 receptor binding / regulation of T-helper 1 cell differentiation / negative regulation of T cell extravasation / negative regulation of cellular extravasation / negative regulation of T-helper 17 type immune response / IL-6-type cytokine receptor ligand interactions / leukemia inhibitory factor receptor activity / oncostatin-M receptor activity / MAPK3 (ERK1) activation / MAPK1 (ERK2) activation / Interleukin-27 signaling / triglyceride mobilization / Interleukin-6 signaling / Interleukin-35 Signalling / interleukin-27 receptor activity / negative regulation of type 2 immune response / oncostatin-M receptor complex / regulation of isotype switching to IgG isotypes / ciliary neurotrophic factor receptor binding / interleukin-6 receptor activity / interleukin-6 binding / ciliary neurotrophic factor receptor complex / interleukin-27-mediated signaling pathway / leptin-mediated signaling pathway / interleukin-6 receptor complex / response to Gram-positive bacterium / regulation of Notch signaling pathway / interleukin-6 receptor binding / positive regulation of T-helper 1 type immune response / interleukin-11-mediated signaling pathway / positive regulation of astrocyte differentiation / intestinal epithelial cell development / interleukin-12 receptor complex / interleukin-23 receptor complex / negative regulation of interleukin-17 production / cytokine receptor activity / glycogen metabolic process / neuronal cell body membrane / interleukin-6-mediated signaling pathway / regulation of T cell proliferation / positive regulation of Notch signaling pathway / negative regulation of cytosolic calcium ion concentration / protein tyrosine kinase activator activity / cytokine binding / positive regulation of activated T cell proliferation / positive regulation of smooth muscle cell migration / peptide hormone binding / negative regulation of interleukin-6 production / negative regulation of tumor necrosis factor production / positive regulation of osteoblast differentiation / coreceptor activity / T cell proliferation / positive regulation of T cell proliferation / positive regulation of tyrosine phosphorylation of STAT protein / positive regulation of defense response to virus by host / cytokine activity / cytokine-mediated signaling pathway / positive regulation of type II interferon production / cell body / scaffold protein binding / negative regulation of neuron apoptotic process / receptor complex / defense response to Gram-positive bacterium / inflammatory response / membrane raft / external side of plasma membrane / innate immune response / signaling receptor binding / neuronal cell body / dendrite / positive regulation of cell population proliferation / cell surface / signal transduction / extracellular space / extracellular region / identical protein binding / plasma membrane / cytoplasm / cytosol
Similarity search - Function
Interleukin-27 alpha / Type I cytokine receptor, cytokine-binding domain / Interleukin-6 receptor alpha chain, binding / Immunoglobulin C2-set-like, ligand-binding / Ig-like C2-type domain / Long hematopoietin receptor, soluble alpha chain, conserved site / Long hematopoietin receptor, soluble alpha chains family signature. / Interferon/interleukin receptor domain / Long hematopoietin receptor, Gp130 family 2, conserved site / Interferon-alpha/beta receptor, fibronectin type III ...Interleukin-27 alpha / Type I cytokine receptor, cytokine-binding domain / Interleukin-6 receptor alpha chain, binding / Immunoglobulin C2-set-like, ligand-binding / Ig-like C2-type domain / Long hematopoietin receptor, soluble alpha chain, conserved site / Long hematopoietin receptor, soluble alpha chains family signature. / Interferon/interleukin receptor domain / Long hematopoietin receptor, Gp130 family 2, conserved site / Interferon-alpha/beta receptor, fibronectin type III / Long hematopoietin receptor, gp130 family signature. / Four-helical cytokine-like, core / Fibronectin type III domain / Fibronectin type 3 domain / Fibronectin type-III domain profile. / Fibronectin type III / Fibronectin type III superfamily / Immunoglobulin-like fold
Similarity search - Domain/homology
Interleukin-27 subunit beta / Interleukin-27 receptor subunit alpha / Interleukin-6 receptor subunit beta / Interleukin-27 subunit alpha
Similarity search - Component
Biological speciesMus musculus (house mouse)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 4 Å
AuthorsJin, Y. / Gardner, S. / Bubeck, D.
Funding support United Kingdom, European Union, 2items
OrganizationGrant numberCountry
Wellcome Trust202323/Z/16/Z United Kingdom
European Research Council (ERC)206-STGEuropean Union
CitationJournal: EMBO Rep / Year: 2022
Title: Structural insights into the assembly and activation of the IL-27 signaling complex.
Authors: Yibo Jin / Paul K Fyfe / Scott Gardner / Stephan Wilmes / Doryen Bubeck / Ignacio Moraga /
Abstract: Interleukin 27 (IL-27) is a heterodimeric cytokine that elicits potent immunosuppressive responses. Comprised of EBI3 and p28 subunits, IL-27 binds GP130 and IL-27Rα receptor chains to activate the ...Interleukin 27 (IL-27) is a heterodimeric cytokine that elicits potent immunosuppressive responses. Comprised of EBI3 and p28 subunits, IL-27 binds GP130 and IL-27Rα receptor chains to activate the JAK/STAT signaling cascade. However, how these receptors recognize IL-27 and form a complex capable of phosphorylating JAK proteins remains unclear. Here, we used cryo electron microscopy (cryoEM) and AlphaFold modeling to solve the structure of the IL-27 receptor recognition complex. Our data show how IL-27 serves as a bridge connecting IL-27Rα (domains 1-2) with GP130 (domains 1-3) to initiate signaling. While both receptors contact the p28 component of the heterodimeric cytokine, EBI3 stabilizes the complex by binding a positively charged surface of IL-27Rα and Domain 1 of GP130. We find that assembly of the IL-27 receptor recognition complex is distinct from both IL-12 and IL-6 cytokine families and provides a mechanistic blueprint for tuning IL-27 pleiotropic actions.
History
DepositionFeb 23, 2022Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jul 27, 2022Provider: repository / Type: Initial release
Revision 1.1Aug 17, 2022Group: Database references / Category: citation
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Oct 19, 2022Group: Database references / Category: citation / Item: _citation.journal_volume

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Interleukin-6 receptor subunit beta
B: Interleukin-27 subunit beta,Interleukin-27 subunit alpha
C: Interleukin-27 receptor subunit alpha
hetero molecules


Theoretical massNumber of molelcules
Total (without water)113,92210
Polymers111,3583
Non-polymers2,5647
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area7370 Å2
ΔGint16 kcal/mol
Surface area46060 Å2

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Components

#1: Protein Interleukin-6 receptor subunit beta / IL-6 receptor subunit beta / IL-6R subunit beta / IL-6R-beta / IL-6RB / Interleukin-6 signal ...IL-6 receptor subunit beta / IL-6R subunit beta / IL-6R-beta / IL-6RB / Interleukin-6 signal transducer / Membrane glycoprotein 130 / gp130 / Oncostatin-M receptor subunit alpha


Mass: 32914.020 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Gene: Il6st / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q00560
#2: Protein Interleukin-27 subunit beta,Interleukin-27 subunit alpha / IL-27 subunit beta / IL-27B / Epstein-Barr virus-induced gene 3 protein homolog / IL-27 subunit ...IL-27 subunit beta / IL-27B / Epstein-Barr virus-induced gene 3 protein homolog / IL-27 subunit alpha / IL-27-A / IL27-A / p28


Mass: 52475.281 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Gene: Ebi3, Il27b, Il27, Il27a / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: O35228, UniProt: Q8K3I6
#3: Protein Interleukin-27 receptor subunit alpha / IL-27 receptor subunit alpha / IL-27R subunit alpha / IL-27R-alpha / IL-27RA / Type I T-cell ...IL-27 receptor subunit alpha / IL-27R subunit alpha / IL-27R-alpha / IL-27RA / Type I T-cell cytokine receptor / TCCR / WSX-1


Mass: 25968.398 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Gene: Il27ra, Tccr, Wsx1 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: O70394
#4: Polysaccharide
2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 424.401 Da / Num. of mol.: 5
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DGlcpNAcb1-4DGlcpNAcb1-ROHGlycam Condensed SequenceGMML 1.0
WURCS=2.0/1,2,1/[a2122h-1b_1-5_2*NCC/3=O]/1-1/a4-b1WURCSPDB2Glycan 1.1.0
[][D-1-deoxy-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{}}LINUCSPDB-CARE
#5: Sugar ChemComp-NAG / 2-acetamido-2-deoxy-beta-D-glucopyranose / N-acetyl-beta-D-glucosamine / 2-acetamido-2-deoxy-beta-D-glucose / 2-acetamido-2-deoxy-D-glucose / 2-acetamido-2-deoxy-glucose / N-ACETYL-D-GLUCOSAMINE


Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C8H15NO6
IdentifierTypeProgram
DGlcpNAcbCONDENSED IUPAC CARBOHYDRATE SYMBOLGMML 1.0
N-acetyl-b-D-glucopyranosamineCOMMON NAMEGMML 1.0
b-D-GlcpNAcIUPAC CARBOHYDRATE SYMBOLPDB-CARE 1.0
GlcNAcSNFG CARBOHYDRATE SYMBOLGMML 1.0
Has ligand of interestN

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: IL-27 Signalling complex / Type: COMPLEX / Entity ID: #1-#3 / Source: RECOMBINANT
Molecular weightValue: 0.1 MDa / Experimental value: NO
Source (natural)Organism: Mus musculus (house mouse)
Source (recombinant)Organism: Spodoptera frugiperda (fall armyworm)
Buffer solutionpH: 7.2 / Details: Solutions were made fresh and 0.2um filtered
Buffer component
IDConc.NameFormulaBuffer-ID
120 mMHEPESHEPES1
2150 mMSodium chlorideNaCl1
SpecimenConc.: 0.1 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES / Details: 0.8mg/ml
Specimen supportGrid material: GOLD / Grid mesh size: 300 divisions/in. / Grid type: EMS Lacey Carbon
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 293 K / Details: Blot time 2s, blot force -2

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal magnification: 81000 X / Nominal defocus max: 3500 nm / Nominal defocus min: 500 nm / Cs: 2.7 mm / C2 aperture diameter: 70 µm / Alignment procedure: COMA FREE
Specimen holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingAverage exposure time: 3.5 sec. / Electron dose: 50 e/Å2 / Film or detector model: GATAN K3 (6k x 4k) / Num. of grids imaged: 2 / Num. of real images: 56523
Image scansWidth: 4092 / Height: 5760

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Processing

Software
NameVersionClassification
phenix.real_space_refine1.20.1_4487refinement
PHENIX1.20.1_4487refinement
EM software
IDNameVersionCategory
2EPU2.11.1.11image acquisition
4cryoSPARC3.3.1CTF correction
7UCSF Chimera1.13.1model fitting
8UCSF ChimeraX1.3model fitting
10ISOLDE1.3model refinement
11PHENIX1.19.2-4158model refinement
12cryoSPARC3.3.1initial Euler assignment
13cryoSPARC3.3.1final Euler assignment
14cryoSPARC3.3.1classification
15cryoSPARC3.3.13D reconstruction
CTF correctionDetails: CTF correction was performed following 3D reconstruction. Local CTF refinement was carried out during refinement
Type: NONE
Particle selectionNum. of particles selected: 1811398
SymmetryPoint symmetry: C1 (asymmetric)
3D reconstructionResolution: 4 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 208431 / Algorithm: BACK PROJECTION
Details: Final reconstruction was performed using local refinement in cryoSPARC.
Num. of class averages: 1 / Symmetry type: POINT
Atomic model buildingProtocol: FLEXIBLE FIT / Space: REAL
Details: Initial fitting was performed using Chimera and ChimeraX. Then ISOLDE and Phenix real space refine were used to refine the model.
RefinementCross valid method: NONE
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
Displacement parametersBiso mean: 195.98 Å2
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00457233
ELECTRON MICROSCOPYf_angle_d0.92469861
ELECTRON MICROSCOPYf_chiral_restr0.06141113
ELECTRON MICROSCOPYf_plane_restr0.01321246
ELECTRON MICROSCOPYf_dihedral_angle_d14.1052673

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