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- PDB-7u7n: IL-27 quaternary receptor signaling complex -

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Basic information

Entry
Database: PDB / ID: 7u7n
TitleIL-27 quaternary receptor signaling complex
Components
  • (Interleukin-27 subunit ...) x 2
  • Interleukin-27 receptor subunit alpha
  • Interleukin-6 receptor subunit beta
KeywordsCYTOKINE / Cytokine Receptor Complex / IL-27
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 T-helper 17 type immune response / interleukin-27 receptor activity / negative regulation of type 2 immune response / oncostatin-M receptor complex / regulation of isotype switching to IgG isotypes / interleukin-11 receptor activity / interleukin-11 binding ...interleukin-27 receptor binding / regulation of T-helper 1 cell differentiation / negative regulation of T cell extravasation / negative regulation of T-helper 17 type immune response / interleukin-27 receptor activity / negative regulation of type 2 immune response / oncostatin-M receptor complex / regulation of isotype switching to IgG isotypes / interleukin-11 receptor activity / interleukin-11 binding / oncostatin-M-mediated signaling pathway / ciliary neurotrophic factor receptor activity / ciliary neurotrophic factor receptor binding / negative regulation of interleukin-6-mediated signaling pathway / leukemia inhibitory factor signaling pathway / ciliary neurotrophic factor receptor complex / interleukin-27-mediated signaling pathway / ciliary neurotrophic factor-mediated signaling pathway / interleukin-6 receptor complex / response to Gram-positive bacterium / interleukin-11-mediated signaling pathway / positive regulation of T-helper 1 type immune response / T-helper 17 cell lineage commitment / positive regulation of adaptive immune response / positive regulation of alpha-beta T cell proliferation / positive regulation of acute inflammatory response / positive regulation of astrocyte differentiation / intestinal epithelial cell development / positive regulation of platelet aggregation / negative regulation of interleukin-17 production / Interleukin-35 Signalling / Interleukin-27 signaling / IL-6-type cytokine receptor ligand interactions / cytokine receptor activity / T-helper 1 type immune response / glycogen metabolic process / Interleukin-6 signaling / interleukin-6-mediated signaling pathway / regulation of T cell proliferation / cytokine binding / positive regulation of Notch signaling pathway / protein tyrosine kinase activator activity / positive regulation of cardiac muscle hypertrophy / MAPK3 (ERK1) activation / growth factor binding / MAPK1 (ERK2) activation / negative regulation of interleukin-6 production / humoral immune response / negative regulation of tumor necrosis factor production / positive regulation of vascular endothelial growth factor production / positive regulation of osteoblast differentiation / coreceptor activity / T cell proliferation / positive regulation of tyrosine phosphorylation of STAT protein / positive regulation of defense response to virus by host / positive regulation of T cell proliferation / cytokine activity / response to cytokine / cytokine-mediated signaling pathway / transmembrane signaling receptor activity / positive regulation of type II interferon production / scaffold protein binding / negative regulation of neuron apoptotic process / cell surface receptor signaling pathway / receptor complex / defense response to Gram-positive bacterium / immune response / inflammatory response / membrane raft / endoplasmic reticulum lumen / external side of plasma membrane / signaling receptor binding / innate immune response / dendrite / neuronal cell body / positive regulation of cell population proliferation / negative regulation of apoptotic process / cell surface / extracellular space / extracellular exosome / extracellular region / membrane / identical protein binding / plasma membrane / cytosol
Similarity search - Function
Interleukin-27 alpha / Type I cytokine receptor, cytokine-binding domain / Long hematopoietin receptor, soluble alpha chain, conserved site / Interleukin-6 receptor alpha chain, binding / Long hematopoietin receptor, soluble alpha chains family signature. / Immunoglobulin C2-set-like, ligand-binding / Ig-like C2-type domain / Long hematopoietin receptor, Gp130 family 2, conserved site / Long hematopoietin receptor, gp130 family signature. / Four-helical cytokine-like, core ...Interleukin-27 alpha / Type I cytokine receptor, cytokine-binding domain / Long hematopoietin receptor, soluble alpha chain, conserved site / Interleukin-6 receptor alpha chain, binding / Long hematopoietin receptor, soluble alpha chains family signature. / Immunoglobulin C2-set-like, ligand-binding / Ig-like C2-type domain / Long hematopoietin receptor, Gp130 family 2, conserved site / 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-6 receptor subunit beta / Interleukin-27 subunit beta / Interleukin-27 receptor subunit alpha / Interleukin-27 subunit alpha
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.47 Å
AuthorsCaveney, N.A. / Glassman, C.R. / Jude, K.M. / Tsutsumi, N. / Garcia, K.C.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)R01-AI51321 United States
CitationJournal: Elife / Year: 2022
Title: Structure of the IL-27 quaternary receptor signaling complex.
Authors: Nathanael A Caveney / Caleb R Glassman / Kevin M Jude / Naotaka Tsutsumi / K Christopher Garcia /
Abstract: Interleukin 27 (IL-27) is a heterodimeric cytokine that functions to constrain T cell-mediated inflammation and plays an important role in immune homeostasis. Binding of IL-27 to cell surface ...Interleukin 27 (IL-27) is a heterodimeric cytokine that functions to constrain T cell-mediated inflammation and plays an important role in immune homeostasis. Binding of IL-27 to cell surface receptors, IL-27Rα and gp130, results in activation of receptor-associated Janus Kinases and nuclear translocation of Signal Transducer and Activator of Transcription 1 (STAT1) and STAT3 transcription factors. Despite the emerging therapeutic importance of this cytokine axis in cancer and autoimmunity, a molecular blueprint of the IL-27 receptor signaling complex, and its relation to other gp130/IL-12 family cytokines, is currently unclear. We used cryogenic-electron microscopy to determine the quaternary structure of IL-27, composed of p28 and Epstein-Barr Virus-Induced 3 (Ebi3) subunits, bound to receptors, IL-27Rα and gp130. The resulting 3.47 Å resolution structure revealed a three-site assembly mechanism nucleated by the central p28 subunit of the cytokine. The overall topology and molecular details of this binding are reminiscent of IL-6 but distinct from related heterodimeric cytokines IL-12 and IL-23. These results indicate distinct receptor assembly mechanisms used by heterodimeric cytokines with important consequences for targeted agonism and antagonism of IL-27 signaling.
History
DepositionMar 7, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 25, 2022Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)107,15512
Polymers103,9244
Non-polymers3,2318
Water0
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

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Protein , 2 types, 2 molecules AB

#1: Protein Interleukin-27 receptor subunit alpha / / IL-27 receptor subunit alpha / IL-27R subunit alpha / IL-27R-alpha / IL-27RA / Cytokine receptor ...IL-27 receptor subunit alpha / IL-27R subunit alpha / IL-27R-alpha / IL-27RA / Cytokine receptor WSX-1 / Cytokine receptor-like 1 / Type I T-cell cytokine receptor / TCCR / ZcytoR1


Mass: 22053.055 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: IL27RA, CRL1, TCCR, WSX1, UNQ296/PRO336 / Production host: Homo sapiens (human) / References: UniProt: Q6UWB1
#2: Protein Interleukin-6 receptor subunit beta / / IL-6 receptor subunit beta / IL-6R subunit beta / IL-6R-beta / IL-6RB / CDw130 / Interleukin-6 ...IL-6 receptor subunit beta / IL-6R subunit beta / IL-6R-beta / IL-6RB / CDw130 / Interleukin-6 signal transducer / Membrane glycoprotein 130 / gp130 / Oncostatin-M receptor subunit alpha


Mass: 34099.535 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: IL6ST / Production host: Homo sapiens (human) / References: UniProt: P40189

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Interleukin-27 subunit ... , 2 types, 2 molecules CD

#3: Protein Interleukin-27 subunit beta / / IL-27 subunit beta / IL-27B / Epstein-Barr virus-induced gene 3 protein / EBV-induced gene 3 protein


Mass: 23209.553 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: EBI3, IL27B / Production host: Homo sapiens (human) / References: UniProt: Q14213
#4: Protein Interleukin-27 subunit alpha / / IL-27 subunit alpha / IL-27-A / IL27-A / Interleukin-30 / p28


Mass: 24562.160 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: IL27, IL27A, IL30 / Production host: Homo sapiens (human) / References: UniProt: Q8NEV9

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Sugars , 4 types, 8 molecules

#5: 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.: 1
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DGlcpNAcb1-4DGlcpNAcb1-Glycam 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
[]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{}}}LINUCSPDB-CARE
#6: Polysaccharide alpha-D-mannopyranose-(1-6)-beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1- ...alpha-D-mannopyranose-(1-6)-beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 748.682 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DManpa1-6DManpb1-4DGlcpNAcb1-4DGlcpNAcb1-Glycam Condensed SequenceGMML 1.0
WURCS=2.0/3,4,3/[a2122h-1b_1-5_2*NCC/3=O][a1122h-1b_1-5][a1122h-1a_1-5]/1-1-2-3/a4-b1_b4-c1_c6-d1WURCSPDB2Glycan 1.1.0
[]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-Manp]{[(6+1)][a-D-Manp]{}}}}}LINUCSPDB-CARE
#7: Polysaccharide beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta- ...beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 586.542 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DManpb1-4DGlcpNAcb1-4DGlcpNAcb1-Glycam Condensed SequenceGMML 1.0
WURCS=2.0/2,3,2/[a2122h-1b_1-5_2*NCC/3=O][a1122h-1b_1-5]/1-1-2/a4-b1_b4-c1WURCSPDB2Glycan 1.1.0
[]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-Manp]{}}}}LINUCSPDB-CARE
#8: 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 / N-Acetylglucosamine


Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 4 / 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

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Details

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 quaternary receptor signaling complex / Type: COMPLEX / Entity ID: #1-#4 / Source: RECOMBINANT
Molecular weightExperimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 8
Buffer component
IDConc.NameFormulaBuffer-ID
120 mMHEPES pH 8.01
2150 mMSodium ChlorideNaClSodium chloride1
SpecimenConc.: 1 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: GOLD / Grid mesh size: 200 divisions/in. / Grid type: Quantifoil R1.2/1.3
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 277.15 K
Details: The grids were blotted for 3 seconds with an offset of 3.

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: OTHER
Electron lensMode: OTHER / Nominal defocus max: 2000 nm / Nominal defocus min: 800 nm
Image recordingElectron dose: 50 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)
EM imaging opticsEnergyfilter name: GIF Bioquantum

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Processing

SoftwareName: PHENIX / Version: 1.20_4459: / Classification: refinement
EM software
IDNameCategory
1cryoSPARCparticle selection
2SerialEMimage acquisition
4cryoSPARCCTF correction
7UCSF ChimeraXmodel fitting
9cryoSPARCinitial Euler assignment
10cryoSPARCfinal Euler assignment
12cryoSPARC3D reconstruction
13PHENIXmodel refinement
14Cootmodel refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNum. of particles selected: 6387370
3D reconstructionResolution: 3.47 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 548147 / Symmetry type: POINT

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