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- EMDB-27641: The structure of the interleukin 11 signalling complex, truncated... -

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Entry
Database: EMDB / ID: EMD-27641
TitleThe structure of the interleukin 11 signalling complex, truncated gp130
Map dataThe structure of the interleukin 11 signalling complex, truncated gp130
Sample
  • Complex: Interleukin 11 signalling complex
    • Complex: gp130
      • Protein or peptide: Interleukin-6 receptor subunit beta
    • Complex: Interleukin-11 receptor subunit alpha
      • Protein or peptide: Interleukin-11 receptor subunit alpha
    • Complex: Interleukin-11
      • Protein or peptide: Interleukin-11
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
Keywordscomplex / IL-6 family cytokine / gp130 / glycoprotein 130 / glycoprotein / CYTOKINE
Function / homology
Function and homology information


interleukin-11 receptor binding / ciliary neurotrophic factor receptor activity / oncostatin-M-mediated signaling pathway / leukemia inhibitory factor signaling pathway / negative regulation of interleukin-6-mediated signaling pathway / oncostatin-M receptor complex / interleukin-27 receptor activity / ciliary neurotrophic factor receptor binding / ciliary neurotrophic factor-mediated signaling pathway / interleukin-11 receptor activity ...interleukin-11 receptor binding / ciliary neurotrophic factor receptor activity / oncostatin-M-mediated signaling pathway / leukemia inhibitory factor signaling pathway / negative regulation of interleukin-6-mediated signaling pathway / oncostatin-M receptor complex / interleukin-27 receptor activity / ciliary neurotrophic factor receptor binding / ciliary neurotrophic factor-mediated signaling pathway / interleukin-11 receptor activity / interleukin-11 binding / interleukin-27-mediated signaling pathway / ciliary neurotrophic factor receptor complex / interleukin-6 receptor complex / megakaryocyte differentiation / head development / negative regulation of hormone secretion / interleukin-11-mediated signaling pathway / T-helper 17 cell lineage commitment / developmental process / positive regulation of adaptive immune response / positive regulation of acute inflammatory response / positive regulation of astrocyte differentiation / intestinal epithelial cell development / positive regulation of platelet aggregation / IL-6-type cytokine receptor ligand interactions / Interleukin-27 signaling / Interleukin-35 Signalling / cytokine receptor activity / cell surface receptor signaling pathway via STAT / positive regulation of peptidyl-tyrosine phosphorylation / Interleukin-6 signaling / growth factor binding / glycogen metabolic process / interleukin-6-mediated signaling pathway / positive regulation of cardiac muscle hypertrophy / positive regulation of Notch signaling pathway / MAPK3 (ERK1) activation / cytokine binding / fat cell differentiation / MAPK1 (ERK2) activation / protein tyrosine kinase activator activity / positive regulation of vascular endothelial growth factor production / positive regulation of peptidyl-serine phosphorylation / positive regulation of osteoblast differentiation / coreceptor activity / positive regulation of T cell proliferation / response to cytokine / embryo implantation / B cell differentiation / cytokine activity / growth factor activity / cytokine-mediated signaling pathway / transmembrane signaling receptor activity / scaffold protein binding / negative regulation of neuron apoptotic process / cell population proliferation / receptor complex / positive regulation of MAPK cascade / membrane raft / external side of plasma membrane / neuronal cell body / positive regulation of cell population proliferation / dendrite / negative regulation of apoptotic process / positive regulation of transcription by RNA polymerase II / extracellular space / extracellular exosome / extracellular region / identical protein binding / membrane / plasma membrane / cytoplasm
Similarity search - Function
Interleukin-11, mammalian / Interleukin-11 / Interleukin 11 / : / : / Type I cytokine receptor, cytokine-binding domain / Long hematopoietin receptor, soluble alpha chain, conserved site / Long hematopoietin receptor, soluble alpha chains family signature. / Interleukin-6 receptor alpha chain, binding / Immunoglobulin C2-set-like, ligand-binding ...Interleukin-11, mammalian / Interleukin-11 / Interleukin 11 / : / : / Type I cytokine receptor, cytokine-binding domain / Long hematopoietin receptor, soluble alpha chain, conserved site / Long hematopoietin receptor, soluble alpha chains family signature. / Interleukin-6 receptor alpha chain, binding / 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 subtype / Immunoglobulin / Ig-like domain profile. / Immunoglobulin-like domain / Immunoglobulin-like domain superfamily / Immunoglobulin-like fold
Similarity search - Domain/homology
Interleukin-11 / Interleukin-6 receptor subunit beta / Interleukin-11 receptor subunit alpha
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.47 Å
AuthorsMetcalfe RD / Hanssen E / Griffin MDW
Funding support Australia, 1 items
OrganizationGrant numberCountry
National Health and Medical Research Council (NHMRC, Australia)APP1147621 Australia
CitationJournal: Nat Commun / Year: 2023
Title: Structures of the interleukin 11 signalling complex reveal gp130 dynamics and the inhibitory mechanism of a cytokine variant.
Authors: Riley D Metcalfe / Eric Hanssen / Ka Yee Fung / Kaheina Aizel / Clara C Kosasih / Courtney O Zlatic / Larissa Doughty / Craig J Morton / Andrew P Leis / Michael W Parker / Paul R Gooley / ...Authors: Riley D Metcalfe / Eric Hanssen / Ka Yee Fung / Kaheina Aizel / Clara C Kosasih / Courtney O Zlatic / Larissa Doughty / Craig J Morton / Andrew P Leis / Michael W Parker / Paul R Gooley / Tracy L Putoczki / Michael D W Griffin /
Abstract: Interleukin (IL-)11, an IL-6 family cytokine, has pivotal roles in autoimmune diseases, fibrotic complications, and solid cancers. Despite intense therapeutic targeting efforts, structural ...Interleukin (IL-)11, an IL-6 family cytokine, has pivotal roles in autoimmune diseases, fibrotic complications, and solid cancers. Despite intense therapeutic targeting efforts, structural understanding of IL-11 signalling and mechanistic insights into current inhibitors are lacking. Here we present cryo-EM and crystal structures of the human IL-11 signalling complex, including the complex containing the complete extracellular domains of the shared IL-6 family β-receptor, gp130. We show that complex formation requires conformational reorganisation of IL-11 and that the membrane-proximal domains of gp130 are dynamic. We demonstrate that the cytokine mutant, IL-11 Mutein, competitively inhibits signalling in human cell lines. Structural shifts in IL-11 Mutein underlie inhibition by altering cytokine binding interactions at all three receptor-engaging sites and abrogating the final gp130 binding step. Our results reveal the structural basis of IL-11 signalling, define the molecular mechanisms of an inhibitor, and advance understanding of gp130-containing receptor complexes, with potential applications in therapeutic development.
History
DepositionJul 17, 2022-
Header (metadata) releaseNov 29, 2023-
Map releaseNov 29, 2023-
UpdateOct 30, 2024-
Current statusOct 30, 2024Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_27641.png

Downloads & links

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Map

FileDownload / File: emd_27641.map.gz / Format: CCP4 / Size: 51.4 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationThe structure of the interleukin 11 signalling complex, truncated gp130
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesX (Sec.)Y (Row.)Z (Col.)
1.31 Å/pix.
x 238 pix.
= 311.78 Å		1.31 Å/pix.
x 238 pix.
= 311.78 Å		1.31 Å/pix.
x 238 pix.
= 311.78 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.31 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 3.0
Minimum - Maximum-30.275486000000001 - 47.310020000000002
Average (Standard dev.)0.000000000002842 (±1.0)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderZYX
Origin000
Dimensions238238238
Spacing238238238
CellA=B=C: 311.78 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: The structure of the interleukin 11 signalling complex,...

Fileemd_27641_half_map_1.map
AnnotationThe structure of the interleukin 11 signalling complex, truncated gp130
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: The structure of the interleukin 11 signalling complex,...

Fileemd_27641_half_map_2.map
AnnotationThe structure of the interleukin 11 signalling complex, truncated gp130
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Interleukin 11 signalling complex

EntireName: Interleukin 11 signalling complex
Components
  • Complex: Interleukin 11 signalling complex
    • Complex: gp130
      • Protein or peptide: Interleukin-6 receptor subunit beta
    • Complex: Interleukin-11 receptor subunit alpha
      • Protein or peptide: Interleukin-11 receptor subunit alpha
    • Complex: Interleukin-11
      • Protein or peptide: Interleukin-11
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose

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Supramolecule #1: Interleukin 11 signalling complex

SupramoleculeName: Interleukin 11 signalling complex / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#3 / Details: 2:2:2 hexameric complex
Molecular weightTheoretical: 182 KDa

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Supramolecule #2: gp130

SupramoleculeName: gp130 / type: complex / ID: 2 / Parent: 1 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)

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Supramolecule #3: Interleukin-11 receptor subunit alpha

SupramoleculeName: Interleukin-11 receptor subunit alpha / type: complex / ID: 3 / Parent: 1 / Macromolecule list: #3
Source (natural)Organism: Homo sapiens (human)

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Supramolecule #4: Interleukin-11

SupramoleculeName: Interleukin-11 / type: complex / ID: 4 / Parent: 1 / Macromolecule list: #2
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Interleukin-6 receptor subunit beta

MacromoleculeName: Interleukin-6 receptor subunit beta / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 34.563961 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: GELLDPCGYI SPESPVVQLH SNFTAVCVLK EKCMDYFHVN ANYIVWKTNH FTIPKEQYTI INRTASSVTF TDIASLNIQL TCNILTFGQ LEQNVYGITI ISGLPPEKPK NLSCIVNEGK KMRCEWDGGR ETHLETNFTL KSEWATHKFA DCKAKRDTPT S CTVDYSTV ...String:
GELLDPCGYI SPESPVVQLH SNFTAVCVLK EKCMDYFHVN ANYIVWKTNH FTIPKEQYTI INRTASSVTF TDIASLNIQL TCNILTFGQ LEQNVYGITI ISGLPPEKPK NLSCIVNEGK KMRCEWDGGR ETHLETNFTL KSEWATHKFA DCKAKRDTPT S CTVDYSTV YFVNIEVWVE AENALGKVTS DHINFDPVYK VKPNPPHNLS VINSEELSSI LKLTWTNPSI KSVIILKYNI QY RTKDAST WSQIPPEDTA STRSSFTVQD LKPFTEYVFR IRCMKEDGKG YWSDWSEEAS GITYED

UniProtKB: Interleukin-6 receptor subunit beta

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Macromolecule #2: Interleukin-11

MacromoleculeName: Interleukin-11 / type: protein_or_peptide / ID: 2 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 18.273289 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString:
GSPDPRAELD STVLLTRSLL ADTRQLAAQL RDKFPADGDH NLDSLPTLAM SAGALGALQL PGVLTRLRAD LLSYLRHVQW LRRAGGSSL KTLEPELGTL QARLDRLLRR LQLLMSRLAL PQPPPDPPAP PLAPPSSAWG GIRAAHAILG GLHLTLDWAV R GLLLLKTR L

UniProtKB: Interleukin-11

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Macromolecule #3: Interleukin-11 receptor subunit alpha

MacromoleculeName: Interleukin-11 receptor subunit alpha / type: protein_or_peptide / ID: 3 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 32.208002 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: GSSPCPQAWG PPGVQYGQPG RSVKLCCPGV TAGDPVSWFR DGEPKLLQGP DSGLGHELVL AQADSTDEGT YICQTLDGAL GGTVTLQLG YPPARPVVSC QAADYENFSC TWSPSQISGL PTRYLTSYRK KTVLGADSQR RSPSTGPWPC PQDPLGAARC V VHGAEFWS ...String:
GSSPCPQAWG PPGVQYGQPG RSVKLCCPGV TAGDPVSWFR DGEPKLLQGP DSGLGHELVL AQADSTDEGT YICQTLDGAL GGTVTLQLG YPPARPVVSC QAADYENFSC TWSPSQISGL PTRYLTSYRK KTVLGADSQR RSPSTGPWPC PQDPLGAARC V VHGAEFWS QYRINVTEVN PLGASTRLLD VSLQSILRPD PPQGLRVESV PGYPRRLRAS WTYPASWPSQ PHFLLKFRLQ YR PAQHPAW STVEPAGLEE VITDAVAGLP HAVRVSARDF LDAGTWSTWS PEAWGTPSTG T

UniProtKB: Interleukin-11 receptor subunit alpha

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Macromolecule #6: 2-acetamido-2-deoxy-beta-D-glucopyranose

MacromoleculeName: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 6 / Number of copies: 4 / Formula: NAG
Molecular weightTheoretical: 221.208 Da
Chemical component information

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

Concentration0.5 mg/mL
BufferpH: 8.5
Component:
ConcentrationNameFormula
0.02 mMTris buffer
0.15 mMSodium chlorideNaCl

Details: TBS pH 85
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TALOS ARCTICA
Image recordingFilm or detector model: GATAN K2 QUANTUM (4k x 4k) / Average electron dose: 52.0 e/Å2
Electron beamAcceleration voltage: 200 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 2.0 µm / Nominal defocus min: 0.8 µm
Experimental equipment
Model: Talos Arctica / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 3082563
Startup modelType of model: NONE
Final reconstructionApplied symmetry - Point group: C2 (2 fold cyclic) / Resolution.type: BY AUTHOR / Resolution: 3.47 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 204455
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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