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- PDB-8qy6: Structure of interleukin 6 (gp130 P496L mutant). -

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Basic information

Entry
Database: PDB / ID: 8qy6
TitleStructure of interleukin 6 (gp130 P496L mutant).
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 / IL-6-type cytokine receptor ligand interactions / glucagon secretion / leukemia inhibitory factor receptor activity / positive regulation of interleukin-21 production / MAPK3 (ERK1) activation / MAPK1 (ERK2) activation / Interleukin-27 signaling ...oncostatin-M receptor activity / ciliary neurotrophic factor binding / regulation of astrocyte activation / IL-6-type cytokine receptor ligand interactions / glucagon secretion / leukemia inhibitory factor receptor activity / positive regulation of interleukin-21 production / MAPK3 (ERK1) activation / MAPK1 (ERK2) activation / Interleukin-27 signaling / triglyceride mobilization / interleukin-6 receptor activity / interleukin-6 binding / regulation of glucagon secretion / Interleukin-6 signaling / hepatic immune response / negative regulation of interleukin-1-mediated signaling pathway / Interleukin-35 Signalling / regulation of vascular endothelial growth factor production / negative regulation of primary miRNA processing / oncostatin-M receptor complex / : / ciliary neurotrophic factor receptor binding / T follicular helper cell differentiation / interleukin-11 receptor activity / interleukin-11 binding / ciliary neurotrophic factor-mediated signaling pathway / germinal center B cell differentiation / ciliary neurotrophic factor receptor complex / interleukin-27-mediated signaling pathway / interleukin-6 receptor complex / positive regulation of extracellular matrix disassembly / 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 / regulation of Notch signaling pathway / interleukin-6 receptor binding / negative regulation of collagen biosynthetic process / endocrine pancreas development / interleukin-11-mediated signaling pathway / positive regulation of B cell activation / inflammatory response to wounding / T-helper 17 cell lineage commitment / positive regulation of T-helper 2 cell cytokine production / 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 astrocyte differentiation / positive regulation of neuroinflammatory response / 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 / cytokine receptor activity / negative regulation of bone resorption / positive regulation of leukocyte adhesion to vascular endothelial cell / CD163 mediating an anti-inflammatory response / positive regulation of immunoglobulin production / glycogen metabolic process / Interleukin-6 signaling / maintenance of blood-brain barrier / interleukin-6-mediated signaling pathway / positive regulation of Notch signaling pathway / protein tyrosine kinase activator activity / negative regulation of fat cell differentiation / negative regulation of cytosolic calcium ion concentration / neuronal cell body membrane / positive regulation of smooth muscle cell migration / MAPK3 (ERK1) activation / monocyte chemotaxis / cytokine binding / positive regulation of interleukin-17 production / Interleukin-10 signaling / 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 / positive regulation of T cell proliferation / response to glucocorticoid / positive regulation of tyrosine phosphorylation of STAT protein / positive regulation of chemokine production / positive regulation of glial cell proliferation / extrinsic apoptotic signaling pathway / regulation of insulin secretion / response to cytokine
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 / Interleukin-6 receptor alpha chain, binding / 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 / Interleukin-6 receptor alpha chain, binding / Long hematopoietin receptor, soluble alpha chain, conserved site / 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 / 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: 3.16 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

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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)360,52118
Polymers355,8356
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 "E"
d_2ens_2chain "B"
d_1ens_3chain "F"
d_2ens_3chain "C"

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_2LEULEUMETMETED19 - 18447 - 212
d_21ens_2LEULEUMETMETBB19 - 18447 - 212
d_11ens_3GLUGLUTRPTRPFE96 - 296115 - 315
d_21ens_3GLUGLUTRPTRPCC96 - 296115 - 315

NCS ensembles :
ID
ens_1
ens_2
ens_3

NCS oper:
IDCodeMatrixVector
1given(-0.9999847611, 0.00517443955486, -0.00192425148701), (-0.00516631968503, -0.999977829905, -0.00420105225627), (-0.00194594691714, -0.00419104693851, 0.999989324151)474.519848309, 477.358699521, 1.75382933125
2given(-0.999885480052, -0.0136106635338, -0.00661639017353), (0.0135132752, -0.999802859785, 0.0145476100549), (-0.00681308844263, 0.0144565349621, 0.999872287056)479.438447682, 468.077330211, -2.08924200025
3given(-0.999686318042, 0.00610331606038, -0.0242902254414), (-0.00652494035714, -0.999828766658, 0.017316538824), (-0.0241803778354, 0.0174695992104, 0.999554962186)479.549858741, 471.348829258, 0.409008730032

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Components

#1: Protein Interleukin-6 receptor subunit beta


Mass: 102568.906 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

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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: 3.16 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 491673 / Symmetry type: POINT
RefinementCross valid method: NONE
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
Displacement parametersBiso mean: 25.9 Å2
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.003615670
ELECTRON MICROSCOPYf_angle_d0.754521318
ELECTRON MICROSCOPYf_chiral_restr0.05212436
ELECTRON MICROSCOPYf_plane_restr0.0092694
ELECTRON MICROSCOPYf_dihedral_angle_d7.41431952
Refine LS restraints NCS
Ens-IDDom-IDAsym-IDAuth asym-IDRefine-IDTypeRms dev position (Å)
ens_1d_2AAELECTRON MICROSCOPYNCS constraints1.49667366283E-11
ens_2d_2DEELECTRON MICROSCOPYNCS constraints8.90959817019E-13
ens_3d_2EFELECTRON MICROSCOPYNCS constraints6.01966905256E-13

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