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- EMDB-27221: Cryo-EM map of human LIF signaling complex with full extracellula... -

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Basic information

Entry
Database: EMDB / ID: EMD-27221
TitleCryo-EM map of human LIF signaling complex with full extracellular domains
Map dataLIF complex main map
Sample
  • Complex: Human LIF in complex with gp130 and LIFR
    • Protein or peptide: Leukemia inhibitory factor
    • Protein or peptide: Interleukin-6 receptor subunit beta
    • Protein or peptide: Leukemia inhibitory factor receptor
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
Keywordscytokine signaling / LIF / gp130 / LIFR / CYTOKINE
Function / homology
Function and homology information


leukemia inhibitory factor receptor binding / positive regulation of mesenchymal to epithelial transition involved in metanephros morphogenesis / meiotic nuclear division / leukemia inhibitory factor receptor activity / interleukin-27 receptor activity / ciliary neurotrophic factor receptor activity / oncostatin-M-mediated signaling pathway / muscle organ morphogenesis / trophoblast giant cell differentiation / negative regulation of meiotic nuclear division ...leukemia inhibitory factor receptor binding / positive regulation of mesenchymal to epithelial transition involved in metanephros morphogenesis / meiotic nuclear division / leukemia inhibitory factor receptor activity / interleukin-27 receptor activity / ciliary neurotrophic factor receptor activity / oncostatin-M-mediated signaling pathway / muscle organ morphogenesis / trophoblast giant cell differentiation / negative regulation of meiotic nuclear division / leukemia inhibitory factor signaling pathway / negative regulation of interleukin-6-mediated signaling pathway / oncostatin-M receptor complex / RUNX1 regulates transcription of genes involved in interleukin signaling / ciliary neurotrophic factor receptor binding / ciliary neurotrophic factor-mediated signaling pathway / interleukin-11 receptor activity / interleukin-11 binding / ciliary neurotrophic factor receptor complex / regulation of metanephric nephron tubule epithelial cell differentiation / interleukin-6 receptor complex / interleukin-27-mediated signaling pathway / negative regulation of hormone secretion / lung vasculature development / interleukin-11-mediated signaling pathway / positive regulation of receptor signaling pathway via STAT / T-helper 17 cell lineage commitment / positive regulation of adaptive immune response / lung lobe morphogenesis / positive regulation of acute inflammatory response / positive regulation of macrophage differentiation / positive regulation of astrocyte differentiation / intestinal epithelial cell development / IL-6-type cytokine receptor ligand interactions / Interleukin-27 signaling / Interleukin-35 Signalling / positive regulation of platelet aggregation / cell surface receptor signaling pathway via STAT / cytokine receptor activity / positive regulation of cell adhesion mediated by integrin / Interleukin-6 signaling / positive regulation of peptidyl-tyrosine phosphorylation / MAPK3 (ERK1) activation / glycogen metabolic process / interleukin-6-mediated signaling pathway / positive regulation of Notch signaling pathway / lung alveolus development / growth factor binding / MAPK1 (ERK2) activation / Interleukin-10 signaling / positive regulation of cardiac muscle hypertrophy / cytokine binding / regulation of cell differentiation / protein tyrosine kinase activator activity / macrophage differentiation / decidualization / somatic stem cell population maintenance / blood vessel remodeling / positive regulation of vascular endothelial growth factor production / neuron development / positive regulation of osteoblast differentiation / positive regulation of T cell proliferation / coreceptor activity / positive regulation of peptidyl-serine phosphorylation / embryo implantation / response to cytokine / cytokine activity / stem cell differentiation / growth factor activity / cytokine-mediated signaling pathway / negative regulation of ERK1 and ERK2 cascade / cell morphogenesis / positive regulation of fibroblast proliferation / fibroblast proliferation / scaffold protein binding / Interleukin-4 and Interleukin-13 signaling / gene expression / negative regulation of neuron apoptotic process / response to hypoxia / receptor complex / cell surface receptor signaling pathway / positive regulation of MAPK cascade / immune response / membrane raft / external side of plasma membrane / signaling receptor binding / negative regulation of cell population proliferation / neuronal cell body / positive regulation of cell population proliferation / dendrite / positive regulation of gene expression / 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 / cytosol
Similarity search - Function
Leukemia inhibitory factor / Leukemia inhibitory factor receptor, N-terminal / Leukemia inhibitory factor receptor N-terminal domain / Leukemia inhibitory factor receptor, D2 domain / : / Leukemia inhibitory factor receptor D2 domain / Leukemia inhibitory factor receptor, Ig-like domain / Leukemia inhibitory factor /oncostatin / Leukemia inhibitory factor /oncostatin, conserved site / LIF / OSM family ...Leukemia inhibitory factor / Leukemia inhibitory factor receptor, N-terminal / Leukemia inhibitory factor receptor N-terminal domain / Leukemia inhibitory factor receptor, D2 domain / : / Leukemia inhibitory factor receptor D2 domain / Leukemia inhibitory factor receptor, Ig-like 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)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.54 Å
AuthorsZhou Y / Franklin MC
Funding support1 items
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, 2022-
Header (metadata) releaseMar 29, 2023-
Map releaseMar 29, 2023-
UpdateMay 21, 2025-
Current statusMay 21, 2025Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_27221.png

Downloads & links

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Map

FileDownload / File: emd_27221.map.gz / Format: CCP4 / Size: 244.1 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationLIF complex main map
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.86 Å/pix.
x 400 pix.
= 344. Å		0.86 Å/pix.
x 400 pix.
= 344. Å		0.86 Å/pix.
x 400 pix.
= 344. Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.86 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.05
Minimum - Maximum-0.22648638 - 0.71610165
Average (Standard dev.)-0.00016360689 (±0.011985596)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions400400400
Spacing400400400
CellA=B=C: 344.0 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: half map A

Fileemd_27221_half_map_1.map
Annotationhalf map A
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: half map B

Fileemd_27221_half_map_2.map
Annotationhalf map B
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Human LIF in complex with gp130 and LIFR

EntireName: Human LIF in complex with gp130 and LIFR
Components
  • Complex: Human LIF in complex with gp130 and LIFR
    • Protein or peptide: Leukemia inhibitory factor
    • Protein or peptide: Interleukin-6 receptor subunit beta
    • Protein or peptide: Leukemia inhibitory factor receptor
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose

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Supramolecule #1: Human LIF in complex with gp130 and LIFR

SupramoleculeName: Human LIF in complex with gp130 and LIFR / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#3
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Leukemia inhibitory factor

MacromoleculeName: Leukemia inhibitory factor / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 19.652777 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString:
PLPITPVNAT CAIRHPCHNN LMNQIRSQLA QLNGSANALF ILYYTAQGEP FPNNLDKLCG PNVTDFPPFH ANGTEKAKLV ELYRIVVYL GTSLGNITRD QKILNPSALS LHSKLNATAD ILRGLLSNVL CRLCSKYHVG HVDVTYGPDT SGKDVFQKKK L GCQLLGKY KQIIAVLAQA F

UniProtKB: Leukemia inhibitory factor

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Macromolecule #2: Interleukin-6 receptor subunit beta

MacromoleculeName: Interleukin-6 receptor subunit beta / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 71.233203 KDa
Recombinant expressionOrganism: Cricetulus griseus (Chinese hamster)
SequenceString: ELLDPCGYIS PESPVVQLHS NFTAVCVLKE KCMDYFHVNA NYIVWKTNHF TIPKEQYTII NRTASSVTFT DIASLNIQLT CNILTFGQL EQNVYGITII SGLPPEKPKN LSCIVNEGKK MRCEWDGGRE THLETNFTLK SEWATHKFAD CKAKRDTPTS C TVDYSTVY ...String:
ELLDPCGYIS PESPVVQLHS NFTAVCVLKE KCMDYFHVNA NYIVWKTNHF TIPKEQYTII NRTASSVTFT DIASLNIQLT CNILTFGQL EQNVYGITII SGLPPEKPKN LSCIVNEGKK MRCEWDGGRE THLETNFTLK SEWATHKFAD CKAKRDTPTS C TVDYSTVY FVNIEVWVEA ENALGKVTSD HINFDPVYKV KPNPPHNLSV INSEELSSIL KLTWTNPSIK SVIILKYNIQ YR TKDASTW SQIPPEDTAS TRSSFTVQDL KPFTEYVFRI RCMKEDGKGY WSDWSEEASG ITYEDRPSKA PSFWYKIDPS HTQ GYRTVQ LVWKTLPPFE ANGKILDYEV TLTRWKSHLQ NYTVNATKLT VNLTNDRYLA TLTVRNLVGK SDAAVLTIPA CDFQ ATHPV MDLKAFPKDN MLWVEWTTPR ESVKKYILEW CVLSDKAPCI TDWQQEDGTV HRTYLRGNLA ESKCYLITVT PVYAD GPGS PESIKAYLKQ APPSKGPTVR TKKVGKNEAV LEWDQLPVDV QNGFIRNYTI FYRTIIGNET AVNVDSSHTE YTLSSL TSD TLYMVRMAAY TDEGGKDGPE FTFTTPKFAQ GEIEEQKLIS EEDLGGEQKL ISEEDLHHHH HH

UniProtKB: Interleukin-6 receptor subunit beta

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Macromolecule #3: Leukemia inhibitory factor receptor

MacromoleculeName: Leukemia inhibitory factor receptor / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 92.834812 KDa
Recombinant expressionOrganism: Cricetulus griseus (Chinese hamster)
SequenceString: QKKGAPHDLK CVTNNLQVWN CSWKAPSGTG RGTDYEVCIE NRSRSCYQLE KTSIKIPALS HGDYEITINS LHDFGSSTSK FTLNEQNVS LIPDTPEILN LSADFSTSTL YLKWNDRGSV FPHRSNVIWE IKVLRKESME LVKLVTHNTT LNGKDTLHHW S WASDMPLE ...String:
QKKGAPHDLK CVTNNLQVWN CSWKAPSGTG RGTDYEVCIE NRSRSCYQLE KTSIKIPALS HGDYEITINS LHDFGSSTSK FTLNEQNVS LIPDTPEILN LSADFSTSTL YLKWNDRGSV FPHRSNVIWE IKVLRKESME LVKLVTHNTT LNGKDTLHHW S WASDMPLE CAIHFVEIRC YIDNLHFSGL EEWSDWSPVK NISWIPDSQT KVFPQDKVIL VGSDITFCCV SQEKVLSALI GH TNCPLIH LDGENVAIKI RNISVSASSG TNVVFTTEDN IFGTVIFAGY PPDTPQQLNC ETHDLKEIIC SWNPGRVTAL VGP RATSYT LVESFSGKYV RLKRAEAPTN ESYQLLFQML PNQEIYNFTL NAHNPLGRSQ STILVNITEK VYPHTPTSFK VKDI NSTAV KLSWHLPGNF AKINFLCEIE IKKSNSVQEQ RNVTIKGVEN SSYLVALDKL NPYTLYTFRI RCSTETFWKW SKWSN KKQH LTTEASPSKG PDTWREWSSD GKNLIIYWKP LPINEANGKI LSYNVSCSSD EETQSLSEIP DPQHKAEIRL DKNDYI ISV VAKNSVGSSP PSKIASMEIP NDDLKIEQVV GMGKGILLTW HYDPNMTCDY VIKWCNSSRS EPCLMDWRKV PSNSTET VI ESDEFRPGIR YNFFLYGCRN QGYQLLRSMI GYIEELAPIV APNFTVEDTS ADSILVKWED IPVEELRGFL RGYLFYFG K GERDTSKMRV LESGRSDIKV KNITDISQKT LRIADLQGKT SYHLVLRAYT DGGVGPEKSM YVVTKENSEQ KLISEEDLG GEQKLISEED LHHHHHH

UniProtKB: Leukemia inhibitory factor receptor

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Macromolecule #5: 2-acetamido-2-deoxy-beta-D-glucopyranose

MacromoleculeName: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 5 / Number of copies: 5 / Formula: NAG
Molecular weightTheoretical: 221.208 Da
Chemical component information

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

BufferpH: 7.5
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 40.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.6 µm / Nominal defocus min: 1.4000000000000001 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: NONE
Final reconstructionApplied symmetry - Point group: C1 (asymmetric) / Resolution.type: BY AUTHOR / Resolution: 3.54 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 171328
Initial angle assignmentType: RANDOM ASSIGNMENT
Final angle assignmentType: MAXIMUM LIKELIHOOD

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