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- PDB-8dpt: The structure of the IL-11 signalling complex, with full-length e... -

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Basic information

Entry
Database: PDB / ID: 8dpt
TitleThe structure of the IL-11 signalling complex, with full-length extracellular gp130
Components
  • Interleukin-11
  • Interleukin-11 receptor subunit alpha
  • Interleukin-6 receptor subunit beta
KeywordsCYTOKINE / Complex / GP130 / glycoprotein 130 / signalling / cancer
Function / homology
Function and homology information


interleukin-11 receptor binding / oncostatin-M-mediated signaling pathway / ciliary neurotrophic factor receptor activity / negative regulation of interleukin-6-mediated signaling pathway / leukemia inhibitory factor signaling pathway / interleukin-27 receptor activity / oncostatin-M receptor complex / ciliary neurotrophic factor receptor binding / interleukin-11 receptor activity / interleukin-11 binding ...interleukin-11 receptor binding / oncostatin-M-mediated signaling pathway / ciliary neurotrophic factor receptor activity / negative regulation of interleukin-6-mediated signaling pathway / leukemia inhibitory factor signaling pathway / interleukin-27 receptor activity / oncostatin-M receptor complex / ciliary neurotrophic factor receptor binding / interleukin-11 receptor activity / interleukin-11 binding / interleukin-6 receptor activity / interleukin-6 binding / ciliary neurotrophic factor-mediated signaling pathway / ciliary neurotrophic factor receptor complex / interleukin-27-mediated signaling pathway / interleukin-6 receptor complex / head development / megakaryocyte differentiation / negative regulation of hormone secretion / interleukin-11-mediated signaling pathway / T-helper 17 cell lineage commitment / positive regulation of adaptive immune response / developmental process / positive regulation of acute inflammatory response / positive regulation of astrocyte differentiation / intestinal epithelial cell development / positive regulation of platelet aggregation / Interleukin-35 Signalling / Interleukin-27 signaling / IL-6-type cytokine receptor ligand interactions / cytokine receptor activity / glycogen metabolic process / interleukin-6-mediated signaling pathway / Interleukin-6 signaling / positive regulation of Notch signaling pathway / protein tyrosine kinase activator activity / positive regulation of cardiac muscle hypertrophy / cytokine binding / fat cell differentiation / MAPK3 (ERK1) activation / growth factor binding / MAPK1 (ERK2) activation / positive regulation of vascular endothelial growth factor production / positive regulation of osteoblast differentiation / coreceptor activity / positive regulation of T cell proliferation / positive regulation of tyrosine phosphorylation of STAT protein / B cell differentiation / response to cytokine / cytokine activity / growth factor activity / cytokine-mediated signaling pathway / transmembrane signaling receptor activity / positive regulation of peptidyl-tyrosine phosphorylation / positive regulation of peptidyl-serine phosphorylation / scaffold protein binding / negative regulation of neuron apoptotic process / cell population proliferation / positive regulation of MAPK cascade / receptor complex / membrane raft / external side of plasma membrane / neuronal cell body / dendrite / positive regulation of cell population proliferation / 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 / 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. / Long hematopoietin receptor, Gp130 family 2, conserved site ...Interleukin-11, mammalian / Interleukin-11 / Interleukin 11 / 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. / 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)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 4 Å
AuthorsMetcalfe, R.D. / Hanssen, E. / Griffin, M.D.W.
Funding support Australia, 1items
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, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 29, 2023Provider: repository / Type: Initial release
Revision 1.1May 1, 2024Group: Database references / Category: citation
Item: _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title

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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-11
C: Interleukin-11 receptor subunit alpha
D: Interleukin-6 receptor subunit beta
E: Interleukin-11
F: Interleukin-11 receptor subunit alpha
hetero molecules


Theoretical massNumber of molelcules
Total (without water)238,26914
Polymers235,3626
Non-polymers2,9078
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: equilibrium centrifugation
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

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Protein , 3 types, 6 molecules ADBECF

#1: 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: 67199.836 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: IL6ST / Plasmid: pFastBac / Cell line (production host): Sf21 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P40189
#2: Protein Interleukin-11 / IL-11 / Adipogenesis inhibitory factor / AGIF


Mass: 18273.289 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: IL11 / Plasmid: pET28b / Production host: Escherichia coli BL21 (bacteria) / Strain (production host): BL21 / References: UniProt: P20809
#3: Protein Interleukin-11 receptor subunit alpha / IL-11 receptor subunit alpha / IL-11R subunit alpha / IL-11R-alpha / IL-11RA


Mass: 32208.002 Da / Num. of mol.: 2 / Mutation: C226S
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: IL11RA / Cell line (production host): Sf21 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q14626

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Sugars , 3 types, 8 molecules

#4: 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-ROHGlycam 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
[][D-1-deoxy-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-Manp]{}}}LINUCSPDB-CARE
#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.: 2
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
#6: 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.: 4
Source method: isolated from a genetically manipulated source
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

Component
IDNameTypeDetailsEntity IDParent-IDSource
1Interleukin 11 signalling complexCOMPLEX2:2:2 hexameric complex of IL-11, IL-11Ra and gp130. Purified from recombinantly expressed and purified proteins.#1-#30MULTIPLE SOURCES
2gp130COMPLEX#11RECOMBINANT
3IL-11RaCOMPLEX#31RECOMBINANT
4IL-11COMPLEX#21RECOMBINANT
Molecular weightValue: 0.29 MDa / Experimental value: YES
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
12Homo sapiens (human)9606
23Homo sapiens (human)9606
34Homo sapiens (human)9606
Source (recombinant)
IDEntity assembly-IDOrganismNcbi tax-IDCellPlasmid
12Spodoptera frugiperda (fall armyworm)7108Sf21pFastBac
34Spodoptera frugiperda (fall armyworm)7108Sf21
23Escherichia coli BL21 (bacteria)511693pET28b
Buffer solutionpH: 8.5
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: GOLD / Grid type: Quantifoil R1.2/1.3
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 95 % / Chamber temperature: 295 K

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Electron microscopy imaging

Experimental equipment
Model: Talos Arctica / Image courtesy: FEI Company
MicroscopyModel: FEI TECNAI ARCTICA
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 200 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2000 nm / Nominal defocus min: 800 nm / Cs: 2.7 mm
Image recordingElectron dose: 52 e/Å2 / Film or detector model: GATAN K2 QUANTUM (4k x 4k)
Image scansMovie frames/image: 40

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Processing

SoftwareName: PHENIX / Version: 1.19.2_4158: / Classification: refinement
CTF correctionType: NONE
SymmetryPoint symmetry: C2 (2 fold cyclic)
3D reconstructionResolution: 4 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 125373 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00413918
ELECTRON MICROSCOPYf_angle_d1.18119040
ELECTRON MICROSCOPYf_dihedral_angle_d4.7791958
ELECTRON MICROSCOPYf_chiral_restr0.0582182
ELECTRON MICROSCOPYf_plane_restr0.0072432

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