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- PDB-8d6a: Cryo-EM structure of human LIF signaling complex: model containin... -

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Basic information

Entry
Database: PDB / ID: 8d6a
TitleCryo-EM structure of human LIF signaling complex: model containing the interaction core region
Components
  • Interleukin-6 receptor subunit beta
  • Leukemia inhibitory factor receptor
  • Leukemia inhibitory factor
KeywordsCYTOKINE / cytokine signaling / LIF / gp130 / LIFR
Function / homology
Function and homology information


leukemia inhibitory factor receptor binding / spongiotrophoblast differentiation / meiotic nuclear division / positive regulation of mesenchymal to epithelial transition involved in metanephros morphogenesis / leukemia inhibitory factor receptor activity / oncostatin-M receptor activity / negative regulation of meiotic nuclear division / muscle organ morphogenesis / interleukin-27 receptor activity / cell surface receptor signaling pathway via STAT ...leukemia inhibitory factor receptor binding / spongiotrophoblast differentiation / meiotic nuclear division / positive regulation of mesenchymal to epithelial transition involved in metanephros morphogenesis / leukemia inhibitory factor receptor activity / oncostatin-M receptor activity / negative regulation of meiotic nuclear division / muscle organ morphogenesis / interleukin-27 receptor activity / cell surface receptor signaling pathway via STAT / oncostatin-M receptor complex / oncostatin-M-mediated signaling pathway / ciliary neurotrophic factor receptor activity / ciliary neurotrophic factor receptor binding / negative regulation of interleukin-6-mediated signaling pathway / leukemia inhibitory factor signaling pathway / interleukin-11 receptor activity / interleukin-11 binding / RUNX1 regulates transcription of genes involved in interleukin signaling / lung vasculature development / ciliary neurotrophic factor receptor complex / interleukin-27-mediated signaling pathway / ciliary neurotrophic factor-mediated signaling pathway / interleukin-6 receptor complex / regulation of metanephric nephron tubule epithelial cell differentiation / positive regulation of peptidyl-serine phosphorylation of STAT protein / negative regulation of hormone secretion / trophoblast giant cell differentiation / interleukin-11-mediated signaling pathway / lung lobe morphogenesis / T-helper 17 cell lineage commitment / positive regulation of adaptive immune response / positive regulation of macrophage differentiation / 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 / positive regulation of cell adhesion mediated by integrin / glycogen metabolic process / Interleukin-6 signaling / interleukin-6-mediated signaling pathway / lung alveolus development / positive regulation of Notch signaling pathway / protein tyrosine kinase activator activity / positive regulation of cardiac muscle hypertrophy / cytokine binding / regulation of cell differentiation / MAPK3 (ERK1) activation / growth factor binding / somatic stem cell population maintenance / Interleukin-10 signaling / MAPK1 (ERK2) activation / macrophage differentiation / decidualization / positive regulation of vascular endothelial growth factor production / neuron development / blood vessel remodeling / positive regulation of osteoblast differentiation / coreceptor activity / positive regulation of T cell proliferation / positive regulation of tyrosine phosphorylation of STAT protein / embryo implantation / response to cytokine / cytokine activity / stem cell differentiation / growth factor activity / cell morphogenesis / negative regulation of ERK1 and ERK2 cascade / cytokine-mediated signaling pathway / positive regulation of peptidyl-tyrosine phosphorylation / positive regulation of fibroblast proliferation / positive regulation of peptidyl-serine phosphorylation / gene expression / fibroblast proliferation / scaffold protein binding / Interleukin-4 and Interleukin-13 signaling / negative regulation of neuron apoptotic process / positive regulation of MAPK cascade / cell surface receptor signaling pathway / receptor complex / response to hypoxia / immune response / membrane raft / negative regulation of cell population proliferation / external side of plasma membrane / signaling receptor binding / neuronal cell body / dendrite / positive regulation of cell population proliferation / positive regulation of gene expression / negative regulation of apoptotic process / positive regulation of transcription by RNA polymerase II / extracellular space / extracellular exosome / extracellular region / membrane
Similarity search - Function
: / Leukemia inhibitory factor receptor, Ig-like domain / Leukemia inhibitory factor / Leukemia inhibitory factor receptor, D2 domain / Leukemia inhibitory factor receptor, N-terminal / Leukemia inhibitory factor receptor D2 domain / Leukemia inhibitory factor receptor N-terminal domain / Leukemia inhibitory factor /oncostatin / Leukemia inhibitory factor /oncostatin, conserved site / LIF / OSM family ...: / Leukemia inhibitory factor receptor, Ig-like domain / Leukemia inhibitory factor / Leukemia inhibitory factor receptor, D2 domain / Leukemia inhibitory factor receptor, N-terminal / Leukemia inhibitory factor receptor D2 domain / Leukemia inhibitory factor receptor N-terminal domain / Leukemia inhibitory factor /oncostatin / Leukemia inhibitory factor /oncostatin, conserved site / LIF / OSM family / LIF / OSM family signature. / leukemia inhibitory factor / 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, 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-like fold
Similarity search - Domain/homology
Leukemia inhibitory factor / Interleukin-6 receptor subunit beta / Leukemia inhibitory factor receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.54 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 6, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 29, 2023Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
D: Leukemia inhibitory factor
A: Interleukin-6 receptor subunit beta
B: Leukemia inhibitory factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)186,94913
Polymers183,7213
Non-polymers3,22810
Water0
1


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

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Components

#1: Protein Leukemia inhibitory factor / / LIF / Differentiation-stimulating factor / D factor / Melanoma-derived LPL inhibitor / MLPLI


Mass: 19652.777 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: LIF, HILDA / Production host: Escherichia coli (E. coli) / References: UniProt: P15018
#2: 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: 71233.203 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: IL6ST / Production host: Cricetulus griseus (Chinese hamster) / References: UniProt: P40189
#3: Protein Leukemia inhibitory factor receptor / / LIF receptor / LIF-R


Mass: 92834.812 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: LIFR / Production host: Cricetulus griseus (Chinese hamster) / References: UniProt: P42702
#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.: 5
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 / N-Acetylglucosamine


Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 5 / 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: Human LIF in complex with gp130 and LIFR / 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 FIELDBright-field microscopy / 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: C1 (asymmetric)
3D reconstructionResolution: 3.54 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 171328 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0028111
ELECTRON MICROSCOPYf_angle_d0.47711049
ELECTRON MICROSCOPYf_dihedral_angle_d18.0961121
ELECTRON MICROSCOPYf_chiral_restr0.0431292
ELECTRON MICROSCOPYf_plane_restr0.0041374

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