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- PDB-8d82: Cryo-EM structure of human IL-6 signaling complex in detergent: m... -

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Basic information

Entry
Database: PDB / ID: 8d82
TitleCryo-EM structure of human IL-6 signaling complex in detergent: model containing full extracellular domains
Components
  • Interleukin-6
  • Interleukin-6 receptor subunit beta
  • Soluble interleukin-6 receptor subunit alpha
KeywordsCYTOKINE / cytokine signaling / IL-6 / IL-6R alpha / gp130
Function / homology
Function and homology information


ciliary neurotrophic factor binding / regulation of astrocyte activation / glucagon secretion / positive regulation of interleukin-21 production / regulation of glucagon secretion / hepatic immune response / interleukin-6 receptor activity / interleukin-6 binding / negative regulation of interleukin-1-mediated signaling pathway / interleukin-27 receptor activity ...ciliary neurotrophic factor binding / regulation of astrocyte activation / glucagon secretion / positive regulation of interleukin-21 production / regulation of glucagon secretion / hepatic immune response / interleukin-6 receptor activity / interleukin-6 binding / negative regulation of interleukin-1-mediated signaling pathway / interleukin-27 receptor activity / ciliary neurotrophic factor receptor activity / oncostatin-M-mediated signaling pathway / regulation of vascular endothelial growth factor production / leukemia inhibitory factor signaling pathway / negative regulation of primary miRNA processing / : / negative regulation of interleukin-6-mediated signaling pathway / oncostatin-M receptor complex / T follicular helper cell differentiation / interleukin-11 receptor activity / interleukin-11 binding / ciliary neurotrophic factor receptor binding / ciliary neurotrophic factor-mediated signaling pathway / germinal center B cell differentiation / ciliary neurotrophic factor receptor complex / interleukin-27-mediated signaling pathway / positive regulation of extracellular matrix disassembly / interleukin-6 receptor complex / positive regulation of receptor signaling pathway via STAT / positive regulation of apoptotic DNA fragmentation / positive regulation of type B pancreatic cell apoptotic process / response to peptidoglycan / regulation of microglial cell activation / hepatocyte proliferation / neutrophil apoptotic process / cell surface receptor signaling pathway via STAT / negative regulation of collagen biosynthetic process / interleukin-6 receptor binding / positive regulation of B cell activation / inflammatory response to wounding / interleukin-11-mediated signaling pathway / T-helper 17 cell lineage commitment / positive regulation of T-helper 2 cell cytokine production / positive regulation of adaptive immune response / endocrine pancreas development / negative regulation of interleukin-8 production / positive regulation of acute inflammatory response / regulation of neuroinflammatory response / positive regulation of glomerular mesangial cell proliferation / vascular endothelial growth factor production / negative regulation of chemokine production / positive regulation of neuroinflammatory response / positive regulation of astrocyte differentiation / positive regulation of leukocyte chemotaxis / intestinal epithelial cell development / neutrophil mediated immunity / positive regulation of platelet aggregation / positive regulation of cytokine production involved in inflammatory response / Interleukin-27 signaling / IL-6-type cytokine receptor ligand interactions / Interleukin-35 Signalling / negative regulation of bone resorption / cytokine receptor activity / positive regulation of leukocyte adhesion to vascular endothelial cell / CD163 mediating an anti-inflammatory response / positive regulation of immunoglobulin production / maintenance of blood-brain barrier / Interleukin-6 signaling / glycogen metabolic process / interleukin-6-mediated signaling pathway / positive regulation of Notch signaling pathway / negative regulation of fat cell differentiation / protein tyrosine kinase activator activity / positive regulation of cardiac muscle hypertrophy / MAPK3 (ERK1) activation / monocyte chemotaxis / growth factor binding / positive regulation of interleukin-17 production / Interleukin-10 signaling / cytokine binding / MAPK1 (ERK2) activation / positive regulation of interleukin-10 production / humoral immune response / negative regulation of lipid storage / Transcriptional Regulation by VENTX / positive regulation of vascular endothelial growth factor production / regulation of angiogenesis / positive regulation of osteoblast differentiation / coreceptor activity / positive regulation of epithelial to mesenchymal transition / response to glucocorticoid / positive regulation of chemokine production / positive regulation of tyrosine phosphorylation of STAT protein / positive regulation of T cell proliferation / positive regulation of glial cell proliferation / extrinsic apoptotic signaling pathway / regulation of insulin secretion / response to cytokine / positive regulation of interleukin-1 beta production / acute-phase response
Similarity search - Function
Interleukin-6 / Interleukin-6/G-CSF/MGF family / Interleukin-6/GCSF/MGF, conserved site / Interleukin-6 / G-CSF / MGF signature. / Interleukin-6/GCSF/MGF / Interleukin-6 homologues / 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 ...Interleukin-6 / Interleukin-6/G-CSF/MGF family / Interleukin-6/GCSF/MGF, conserved site / Interleukin-6 / G-CSF / MGF signature. / Interleukin-6/GCSF/MGF / Interleukin-6 homologues / 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 / Immunoglobulin / Immunoglobulin domain / Fibronectin type III domain / Fibronectin type 3 domain / Immunoglobulin subtype 2 / Immunoglobulin C-2 Type / 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-6 / Interleukin-6 receptor subunit alpha / Interleukin-6 receptor subunit beta
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.22 Å
AuthorsZhou, Y. / Franklin, M.C.
Funding support1items
OrganizationGrant numberCountry
Other private
CitationJournal: Sci Adv / Year: 2023
Title: Structural insights into the assembly of gp130 family cytokine signaling complexes.
Authors: Yi Zhou / Panayiotis E Stevis / Jing Cao / Kei Saotome / Jiaxi Wu / Arielle Glatman Zaretsky / Sokol Haxhinasto / George D Yancopoulos / Andrew J Murphy / Mark W Sleeman / William C Olson / Matthew C Franklin /
Abstract: The interleukin-6 (IL-6) family cytokines signal through gp130 receptor homodimerization or heterodimerization with a second signaling receptor and play crucial roles in various cellular processes. ...The interleukin-6 (IL-6) family cytokines signal through gp130 receptor homodimerization or heterodimerization with a second signaling receptor and play crucial roles in various cellular processes. We determined cryo-electron microscopy structures of five signaling complexes of this family, containing full receptor ectodomains bound to their respective ligands ciliary neurotrophic factor, cardiotrophin-like cytokine factor 1 (CLCF1), leukemia inhibitory factor, IL-27, and IL-6. Our structures collectively reveal similarities and differences in the assembly of these complexes. The acute bends at both signaling receptors in all complexes bring the membrane-proximal domains to a ~30 angstrom range but with distinct distances and orientations. We also reveal how CLCF1 engages its secretion chaperone cytokine receptor-like factor 1. Our data provide valuable insights for therapeutically targeting gp130-mediated signaling.
History
DepositionJun 7, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 29, 2023Provider: repository / Type: Initial release
Revision 1.1Nov 13, 2024Group: Data collection / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / em_admin / pdbx_entry_details / pdbx_modification_feature
Item: _em_admin.last_update / _pdbx_entry_details.has_protein_modification

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
C: Soluble interleukin-6 receptor subunit alpha
D: Interleukin-6
A: Interleukin-6 receptor subunit beta
G: Soluble interleukin-6 receptor subunit alpha
H: Interleukin-6
E: Interleukin-6 receptor subunit beta
hetero molecules


Theoretical massNumber of molelcules
Total (without water)281,46034
Polymers273,2346
Non-polymers8,22628
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein Soluble interleukin-6 receptor subunit alpha / sIL6R


Mass: 38694.320 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: IL6R / Production host: Cricetulus griseus (Chinese hamster) / References: UniProt: P08887
#2: Protein Interleukin-6 / IL-6 / B-cell stimulatory factor 2 / BSF-2 / CTL differentiation factor / CDF / Hybridoma growth ...IL-6 / B-cell stimulatory factor 2 / BSF-2 / CTL differentiation factor / CDF / Hybridoma growth factor / Interferon beta-2 / IFN-beta-2


Mass: 20837.770 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: IL6, IFNB2 / Production host: Escherichia coli (E. coli) / References: UniProt: P05231
#3: 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: 77085.125 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: IL6ST / Production host: Homo sapiens (human) / References: UniProt: P40189
#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.: 10
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
#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.: 18 / 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
Has protein modificationY

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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: Human IL-6 in complex with IL-6R alpha and detergent-solubilized gp130
Type: COMPLEX / Entity ID: #1-#3 / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Cricetulus griseus (Chinese hamster)
Buffer solutionpH: 7.5
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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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 defocus max: 2600 nm / Nominal defocus min: 1400 nm
Image recordingElectron dose: 40 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)

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Processing

SoftwareName: PHENIX / Version: 1.17.1_3660: / Classification: refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
SymmetryPoint symmetry: C2 (2 fold cyclic)
3D reconstructionResolution: 3.22 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 105760 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00217790
ELECTRON MICROSCOPYf_angle_d0.43224210
ELECTRON MICROSCOPYf_dihedral_angle_d18.4732508
ELECTRON MICROSCOPYf_chiral_restr0.042804
ELECTRON MICROSCOPYf_plane_restr0.0033044

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