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- PDB-8qy5: Structure of interleukin 6. -

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Basic information

Entry
Database: PDB / ID: 8qy5
TitleStructure of interleukin 6.
Components
  • Interleukin-6
  • Interleukin-6 receptor subunit alpha
  • Interleukin-6 receptor subunit beta
KeywordsIMMUNE SYSTEM / interleukin / gp130
Function / homology
Function and homology information


oncostatin-M receptor activity / ciliary neurotrophic factor binding / regulation of astrocyte activation / glucagon secretion / positive regulation of interleukin-21 production / IL-6-type cytokine receptor ligand interactions / MAPK3 (ERK1) activation / MAPK1 (ERK2) activation / Interleukin-27 signaling / leukemia inhibitory factor receptor activity ...oncostatin-M receptor activity / ciliary neurotrophic factor binding / regulation of astrocyte activation / glucagon secretion / positive regulation of interleukin-21 production / IL-6-type cytokine receptor ligand interactions / MAPK3 (ERK1) activation / MAPK1 (ERK2) activation / Interleukin-27 signaling / leukemia inhibitory factor receptor activity / regulation of glucagon secretion / hepatic immune response / interleukin-6 receptor activity / interleukin-6 binding / Interleukin-6 signaling / negative regulation of primary miRNA processing / Interleukin-35 Signalling / regulation of vascular endothelial growth factor production / negative regulation of interleukin-1-mediated signaling pathway / oncostatin-M receptor complex / interleukin-27 receptor activity / regulation of microglial cell activation / ciliary neurotrophic factor receptor binding / ciliary neurotrophic factor-mediated signaling pathway / interleukin-11 receptor activity / interleukin-11 binding / ciliary neurotrophic factor receptor complex / interleukin-6 receptor complex / positive regulation of apoptotic DNA fragmentation / positive regulation of type B pancreatic cell apoptotic process / hepatocyte proliferation / germinal center B cell differentiation / response to peptidoglycan / neutrophil apoptotic process / positive regulation of extracellular matrix disassembly / interleukin-6 receptor binding / positive regulation of B cell activation / interleukin-11-mediated signaling pathway / positive regulation of receptor signaling pathway via STAT / T-helper 17 cell lineage commitment / inflammatory response to wounding / regulation of Notch signaling pathway / positive regulation of T-helper 2 cell cytokine production / positive regulation of adaptive immune response / endocrine pancreas development / negative regulation of collagen biosynthetic process / regulation of neuroinflammatory response / vascular endothelial growth factor production / positive regulation of acute inflammatory response / negative regulation of interleukin-8 production / positive regulation of astrocyte differentiation / positive regulation of glomerular mesangial cell proliferation / T follicular helper cell differentiation / negative regulation of chemokine production / positive regulation of neuroinflammatory response / intestinal epithelial cell development / positive regulation of leukocyte chemotaxis / positive regulation of platelet aggregation / neutrophil mediated immunity / positive regulation of cytokine production involved in inflammatory response / cytokine receptor activity / cell surface receptor signaling pathway via STAT / negative regulation of bone resorption / positive regulation of leukocyte adhesion to vascular endothelial cell / CD163 mediating an anti-inflammatory response / positive regulation of peptidyl-tyrosine phosphorylation / 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 / MAPK3 (ERK1) activation / MAPK1 (ERK2) activation / Interleukin-10 signaling / positive regulation of interleukin-17 production / monocyte chemotaxis / protein tyrosine kinase activator activity / humoral immune response / positive regulation of interleukin-10 production / positive regulation of vascular endothelial growth factor production / negative regulation of lipid storage / Transcriptional Regulation by VENTX / positive regulation of peptidyl-serine phosphorylation / regulation of angiogenesis / cell surface receptor signaling pathway via JAK-STAT / positive regulation of osteoblast differentiation / positive regulation of epithelial to mesenchymal transition / response to glucocorticoid / coreceptor activity / positive regulation of chemokine production / positive regulation of DNA-binding transcription factor activity / extrinsic apoptotic signaling pathway / positive regulation of glial cell proliferation / response to cytokine / positive regulation of T cell proliferation / regulation of insulin secretion / positive regulation of translation / positive regulation of interleukin-1 beta production
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 / 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 speciesMus musculus (house mouse)
Homo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.1 Å
AuthorsGardner, S. / Bubeck, D. / Jin, Y.
Funding support United Kingdom, European Union, 4items
OrganizationGrant numberCountry
Wellcome Trust202323/Z/16 United Kingdom
European Research Council (ERC)C-206-STGEuropean Union
Engineering and Physical Sciences Research CouncilEP/X035603/1 United Kingdom
Biotechnology and Biological Sciences Research Council (BBSRC)BB/M011178/1 United Kingdom
Citation
Journal: Nat Commun / Year: 2024
Title: Structural insights into IL-11-mediated signalling and human IL6ST variant-associated immunodeficiency.
Authors: Scott Gardner / Yibo Jin / Paul K Fyfe / Tomas B Voisin / Junel Sotolongo Bellón / Elizabeth Pohler / Jacob Piehler / Ignacio Moraga / Doryen Bubeck /
Abstract: IL-11 and IL-6 activate signalling via assembly of the cell surface receptor gp130; however, it is unclear how signals are transmitted across the membrane to instruct cellular responses. Here we ...IL-11 and IL-6 activate signalling via assembly of the cell surface receptor gp130; however, it is unclear how signals are transmitted across the membrane to instruct cellular responses. Here we solve the cryoEM structure of the IL-11 receptor recognition complex to discover how differences in gp130-binding interfaces may drive signalling outcomes. We explore how mutations in the IL6ST gene encoding for gp130, which cause severe immune deficiencies in humans, impair signalling without blocking cytokine binding. We use cryoEM to solve structures of both IL-11 and IL-6 complexes with a mutant form of gp130 associated with human disease. Together with molecular dynamics simulations, we show that the disease-associated variant led to an increase in flexibility including motion within the cytokine-binding core and increased distance between extracellular domains. However, these distances are minimized as the transmembrane helix exits the membrane, suggesting a stringency in geometry for signalling and dimmer switch mode of action.
#1: Journal: Acta Crystallogr D Struct Biol / Year: 2019
Title: Macromolecular structure determination using X-rays, neutrons and electrons: recent developments in Phenix.
Authors: Dorothee Liebschner / Pavel V Afonine / Matthew L Baker / Gábor Bunkóczi / Vincent B Chen / Tristan I Croll / Bradley Hintze / Li Wei Hung / Swati Jain / Airlie J McCoy / Nigel W Moriarty ...Authors: Dorothee Liebschner / Pavel V Afonine / Matthew L Baker / Gábor Bunkóczi / Vincent B Chen / Tristan I Croll / Bradley Hintze / Li Wei Hung / Swati Jain / Airlie J McCoy / Nigel W Moriarty / Robert D Oeffner / Billy K Poon / Michael G Prisant / Randy J Read / Jane S Richardson / David C Richardson / Massimo D Sammito / Oleg V Sobolev / Duncan H Stockwell / Thomas C Terwilliger / Alexandre G Urzhumtsev / Lizbeth L Videau / Christopher J Williams / Paul D Adams /
Abstract: Diffraction (X-ray, neutron and electron) and electron cryo-microscopy are powerful methods to determine three-dimensional macromolecular structures, which are required to understand biological ...Diffraction (X-ray, neutron and electron) and electron cryo-microscopy are powerful methods to determine three-dimensional macromolecular structures, which are required to understand biological processes and to develop new therapeutics against diseases. The overall structure-solution workflow is similar for these techniques, but nuances exist because the properties of the reduced experimental data are different. Software tools for structure determination should therefore be tailored for each method. Phenix is a comprehensive software package for macromolecular structure determination that handles data from any of these techniques. Tasks performed with Phenix include data-quality assessment, map improvement, model building, the validation/rebuilding/refinement cycle and deposition. Each tool caters to the type of experimental data. The design of Phenix emphasizes the automation of procedures, where possible, to minimize repetitive and time-consuming manual tasks, while default parameters are chosen to encourage best practice. A graphical user interface provides access to many command-line features of Phenix and streamlines the transition between programs, project tracking and re-running of previous tasks.
History
DepositionOct 25, 2023Deposition site: PDBE / Processing site: PDBE
Revision 1.0Feb 21, 2024Provider: repository / Type: Initial release
Revision 1.1Sep 4, 2024Group: Data collection / Database references / Category: citation / citation_author / em_admin
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _em_admin.last_update
Revision 1.2Oct 9, 2024Group: Data collection / Structure summary
Category: 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
A: Interleukin-6 receptor subunit beta
B: Interleukin-6
C: Interleukin-6 receptor subunit alpha
E: Interleukin-6
F: Interleukin-6 receptor subunit alpha
D: Interleukin-6 receptor subunit beta
hetero molecules


Theoretical massNumber of molelcules
Total (without water)360,48918
Polymers355,8036
Non-polymers4,68612
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
d_1ens_1chain "A"
d_2ens_1chain "D"
d_1ens_2chain "B"
d_2ens_2chain "E"
d_1ens_3chain "C"
d_2ens_3chain "F"

NCS domain segments:
Dom-IDComponent-IDEns-IDBeg auth comp-IDBeg label comp-IDEnd auth comp-IDEnd label comp-IDAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
d_11ens_1LEULEUTHRTHRAA24 - 60724 - 607
d_12ens_1NAGNAGNAGNAGGG1
d_13ens_1NAGNAGNAGNAGGG2
d_14ens_1NAGNAGNAGNAGHH1
d_15ens_1NAGNAGNAGNAGHH2
d_16ens_1NAGNAGNAGNAGII1
d_17ens_1NAGNAGNAGNAGII2
d_18ens_1NAGNAGNAGNAGJJ1
d_19ens_1NAGNAGNAGNAGJJ2
d_110ens_1NAGNAGNAGNAGKK1
d_111ens_1NAGNAGNAGNAGKK2
d_112ens_1NAGNAGNAGNAGAQ1001
d_21ens_1LEULEUTHRTHRDF24 - 60724 - 607
d_22ens_1NAGNAGNAGNAGLL1
d_23ens_1NAGNAGNAGNAGLL2
d_24ens_1NAGNAGNAGNAGMM1
d_25ens_1NAGNAGNAGNAGMM2
d_26ens_1NAGNAGNAGNAGNN1
d_27ens_1NAGNAGNAGNAGNN2
d_28ens_1NAGNAGNAGNAGOO1
d_29ens_1NAGNAGNAGNAGOO2
d_210ens_1NAGNAGNAGNAGPP1
d_211ens_1NAGNAGNAGNAGPP2
d_212ens_1NAGNAGNAGNAGDR1001
d_11ens_2LEULEUMETMETBB19 - 18447 - 212
d_21ens_2LEULEUMETMETED19 - 18447 - 212
d_11ens_3GLUGLUTRPTRPCC96 - 296115 - 315
d_21ens_3GLUGLUTRPTRPFE96 - 296115 - 315

NCS ensembles :
ID
ens_1
ens_2
ens_3

NCS oper:
IDCodeMatrixVector
1given(-0.999978426275, 0.00538193729635, -0.00376586454582), (-0.00529415447165, -0.99972272915, -0.022944209479), (-0.00388830467809, -0.0229237774184, 0.999729654214)479.503039458, 486.424513413, 6.82036695045
2given(-0.999895960733, 0.0139406547212, -0.00370484214678), (-0.0139294482609, -0.999898378713, -0.00303359822297), (-0.00374675600134, -0.00298167620264, 0.999988535648)476.680882426, 483.849545274, 1.91267365038
3given(-0.999716553779, -0.00393525507681, -0.023480329362), (0.00376969365206, -0.999967751833, 0.00709117077717), (-0.0235074777303, 0.00700064716307, 0.99969914946)485.854525159, 476.50561787, 5.48713827804

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Components

#1: Protein Interleukin-6 receptor subunit beta


Mass: 102552.867 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Gene: Il6st / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: Q00560
#2: Protein Interleukin-6


Mass: 23743.189 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: IL6 / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: P05231
#3: Protein Interleukin-6 receptor subunit alpha


Mass: 51605.348 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: IL6R / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: P08887
#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.: 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
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: IL-6 signalling complex / Type: COMPLEX / Entity ID: #1-#3 / Source: RECOMBINANT
Molecular weightExperimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Trichoplusia ni (cabbage looper)
Buffer solutionpH: 7.2
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: 2250 nm / Nominal defocus min: 500 nm
Image recordingElectron dose: 50 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

EM softwareName: PHENIX / Version: 1.21rc1_4933 / Category: model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.1 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 1042507 / Symmetry type: POINT
RefinementCross valid method: NONE
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
Displacement parametersBiso mean: 67.33 Å2
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.003515670
ELECTRON MICROSCOPYf_angle_d0.733521320
ELECTRON MICROSCOPYf_chiral_restr0.05092434
ELECTRON MICROSCOPYf_plane_restr0.00952696
ELECTRON MICROSCOPYf_dihedral_angle_d7.67341952
Refine LS restraints NCS
Ens-IDDom-IDAsym-IDAuth asym-IDRefine-IDTypeRms dev position (Å)
ens_1d_2AAELECTRON MICROSCOPYNCS constraints4.81387268071E-12
ens_2d_2BBELECTRON MICROSCOPYNCS constraints1.51340585689E-12
ens_3d_2CCELECTRON MICROSCOPYNCS constraints5.76613995744E-13

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