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- EMDB-27228: Cryo-EM structure of human CNTFR alpha in complex with the Fab fr... -

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Basic information

Entry
Database: EMDB / ID: EMD-27228
TitleCryo-EM structure of human CNTFR alpha in complex with the Fab fragments of two antibodies
Map dataCNTFRa-8938-25311 map
Sample
  • Complex: Human CNTFR alpha in complex with the Fab fragments of two antibodies
    • Protein or peptide: Ciliary neurotrophic factor receptor subunit alpha
    • Protein or peptide: H4H25311P2 antibody Fab fragment light chain
    • Protein or peptide: H4H25311P2 antibody Fab fragment heavy chain
    • Protein or peptide: REGN8938 antibody Fab fragment light chain
    • Protein or peptide: REGN8938 antibody Fab fragment heavy chain
Keywordscytokine signaling / CNTFR alpha / CYTOKINE / antibody / Fab / CYTOKINE-Immune System complex
Function / homology
Function and homology information


CNTFR-CLCF1 complex / skeletal muscle organ development / ciliary neurotrophic factor receptor activity / ciliary neurotrophic factor-mediated signaling pathway / ciliary neurotrophic factor receptor complex / brainstem development / sex differentiation / negative regulation of motor neuron apoptotic process / IL-6-type cytokine receptor ligand interactions / cytokine receptor activity ...CNTFR-CLCF1 complex / skeletal muscle organ development / ciliary neurotrophic factor receptor activity / ciliary neurotrophic factor-mediated signaling pathway / ciliary neurotrophic factor receptor complex / brainstem development / sex differentiation / negative regulation of motor neuron apoptotic process / IL-6-type cytokine receptor ligand interactions / cytokine receptor activity / motor neuron apoptotic process / extrinsic component of membrane / suckling behavior / cytokine binding / nervous system development / negative regulation of neuron apoptotic process / apical plasma membrane / external side of plasma membrane / signaling receptor binding / positive regulation of cell population proliferation / signal transduction / plasma membrane
Similarity search - Function
Long hematopoietin receptor, soluble alpha chain, conserved site / Long hematopoietin receptor, soluble alpha chains family signature. / : / 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 ...Long hematopoietin receptor, soluble alpha chain, conserved site / Long hematopoietin receptor, soluble alpha chains family signature. / : / 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
Ciliary neurotrophic factor receptor subunit alpha
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.93 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 7, 2022-
Header (metadata) releaseMar 29, 2023-
Map releaseMar 29, 2023-
UpdateNov 6, 2024-
Current statusNov 6, 2024Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_27228.png

Downloads & links

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Map

FileDownload / File: emd_27228.map.gz / Format: CCP4 / Size: 149.9 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationCNTFRa-8938-25311 map
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.85 Å/pix.
x 340 pix.
= 289. Å		0.85 Å/pix.
x 340 pix.
= 289. Å		0.85 Å/pix.
x 340 pix.
= 289. Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.85 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.13
Minimum - Maximum-1.3787543 - 1.8818645
Average (Standard dev.)0.00012586458 (±0.03645775)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions340340340
Spacing340340340
CellA=B=C: 289.0 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: Half Map 1

Fileemd_27228_half_map_1.map
AnnotationHalf Map 1
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Half Map 2

Fileemd_27228_half_map_2.map
AnnotationHalf Map 2
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 CNTFR alpha in complex with the Fab fragments of two antibodies

EntireName: Human CNTFR alpha in complex with the Fab fragments of two antibodies
Components
  • Complex: Human CNTFR alpha in complex with the Fab fragments of two antibodies
    • Protein or peptide: Ciliary neurotrophic factor receptor subunit alpha
    • Protein or peptide: H4H25311P2 antibody Fab fragment light chain
    • Protein or peptide: H4H25311P2 antibody Fab fragment heavy chain
    • Protein or peptide: REGN8938 antibody Fab fragment light chain
    • Protein or peptide: REGN8938 antibody Fab fragment heavy chain

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Supramolecule #1: Human CNTFR alpha in complex with the Fab fragments of two antibodies

SupramoleculeName: Human CNTFR alpha in complex with the Fab fragments of two antibodies
type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Ciliary neurotrophic factor receptor subunit alpha

MacromoleculeName: Ciliary neurotrophic factor receptor subunit alpha / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 39.170848 KDa
Recombinant expressionOrganism: Cricetulus griseus (Chinese hamster)
SequenceString: QRHSPQEAPH VQYERLGSDV TLPCGTANWD AAVTWRVNGT DLAPDLLNGS QLVLHGLELG HSGLYACFHR DSWHLRHQVL LHVGLPPRE PVLSCRSNTY PKGFYCSWHL PTPTYIPNTF NVTVLHGSKI MVCEKDPALK NRCHIRYMHL FSTIKYKVSI S VSNALGHN ...String:
QRHSPQEAPH VQYERLGSDV TLPCGTANWD AAVTWRVNGT DLAPDLLNGS QLVLHGLELG HSGLYACFHR DSWHLRHQVL LHVGLPPRE PVLSCRSNTY PKGFYCSWHL PTPTYIPNTF NVTVLHGSKI MVCEKDPALK NRCHIRYMHL FSTIKYKVSI S VSNALGHN ATAITFDEFT IVKPDPPENV VARPVPSNPR RLEVTWQTPS TWPDPESFPL KFFLRYRPLI LDQWQHVELS DG TAHTITD AYAGKEYIIQ VAAKDNEIGT WSDWSVAAHA TPWTEEPRHL TTEAQAAETT TSTTSSLAPP PTTKICDPGE LGS EQKLIS EEDLGGEQKL ISEEDLHHHH HH

UniProtKB: Ciliary neurotrophic factor receptor subunit alpha

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Macromolecule #2: H4H25311P2 antibody Fab fragment light chain

MacromoleculeName: H4H25311P2 antibody Fab fragment light chain / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 23.446953 KDa
Recombinant expressionOrganism: Cricetulus griseus (Chinese hamster)
SequenceString: EIVLTQSPGT LSLSPGERAT LSCRASQSVS SSYLAWYQQK PGQAPRLLIY GASSRATGIP DRFSGSGSGT DFTLTISRLE PEDFAVYYC QQYGSSPWTF GQGTKVEIKR TVAAPSVFIF PPSDEQLKSG TASVVCLLNN FYPREAKVQW KVDNALQSGN S QESVTEQD ...String:
EIVLTQSPGT LSLSPGERAT LSCRASQSVS SSYLAWYQQK PGQAPRLLIY GASSRATGIP DRFSGSGSGT DFTLTISRLE PEDFAVYYC QQYGSSPWTF GQGTKVEIKR TVAAPSVFIF PPSDEQLKSG TASVVCLLNN FYPREAKVQW KVDNALQSGN S QESVTEQD SKDSTYSLSS TLTLSKADYE KHKVYACEVT HQGLSSPVTK SFNRGEC

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Macromolecule #3: H4H25311P2 antibody Fab fragment heavy chain

MacromoleculeName: H4H25311P2 antibody Fab fragment heavy chain / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 23.529438 KDa
Recombinant expressionOrganism: Cricetulus griseus (Chinese hamster)
SequenceString: QVQLVESGGG VVQPGRSLRL SCVASGFTFS TSVMHWVRQA PGKGLEWVAN IWYDGINKFY VDSVKGRFTI SRDNSKNTLY LQMNSLRAE DTAVYYCARE FWSAFDLWGQ GTMVTVSSAS TKGPSVFPLA PCSRSTSEST AALGCLVKDY FPEPVTVSWN S GALTSGVH ...String:
QVQLVESGGG VVQPGRSLRL SCVASGFTFS TSVMHWVRQA PGKGLEWVAN IWYDGINKFY VDSVKGRFTI SRDNSKNTLY LQMNSLRAE DTAVYYCARE FWSAFDLWGQ GTMVTVSSAS TKGPSVFPLA PCSRSTSEST AALGCLVKDY FPEPVTVSWN S GALTSGVH TFPAVLQSSG LYSLSSVVTV PSSSLGTKTY TCNVDHKPSN TKVDKRVES

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Macromolecule #4: REGN8938 antibody Fab fragment light chain

MacromoleculeName: REGN8938 antibody Fab fragment light chain / type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 23.438967 KDa
Recombinant expressionOrganism: Cricetulus griseus (Chinese hamster)
SequenceString: DIQMTQSPSS LSASVGDRVT ITCRASQSIS SYLNWYQQKP GKAPKLLIYA ASSLQSGVPS RFSGSGSGTD FTLTISSLQP EDFATYYCQ QSYSTPPITF GQGTRLEIKR TVAAPSVFIF PPSDEQLKSG TASVVCLLNN FYPREAKVQW KVDNALQSGN S QESVTEQD ...String:
DIQMTQSPSS LSASVGDRVT ITCRASQSIS SYLNWYQQKP GKAPKLLIYA ASSLQSGVPS RFSGSGSGTD FTLTISSLQP EDFATYYCQ QSYSTPPITF GQGTRLEIKR TVAAPSVFIF PPSDEQLKSG TASVVCLLNN FYPREAKVQW KVDNALQSGN S QESVTEQD SKDSTYSLSS TLTLSKADYE KHKVYACEVT HQGLSSPVTK SFNRGEC

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Macromolecule #5: REGN8938 antibody Fab fragment heavy chain

MacromoleculeName: REGN8938 antibody Fab fragment heavy chain / type: protein_or_peptide / ID: 5 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 23.922656 KDa
Recombinant expressionOrganism: Cricetulus griseus (Chinese hamster)
SequenceString: QVQLVESGGD VVQPGRSLRL SCAASGFTFS YYGMHWVRQP PGKGLEWVTI ISFDGSQKYY ADSVKGRFTI SRDNSKNTVF LQMNSLRTE DTGFYYCAAQ SSTWPEYFQY WGQGTLVTVS SASTKGPSVF PLAPCSRSTS ESTAALGCLV KDYFPEPVTV S WNSGALTS ...String:
QVQLVESGGD VVQPGRSLRL SCAASGFTFS YYGMHWVRQP PGKGLEWVTI ISFDGSQKYY ADSVKGRFTI SRDNSKNTVF LQMNSLRTE DTGFYYCAAQ SSTWPEYFQY WGQGTLVTVS SASTKGPSVF PLAPCSRSTS ESTAALGCLV KDYFPEPVTV S WNSGALTS GVHTFPAVLQ SSGLYSLSSV VTVPSSSLGT KTYTCNVDHK PSNTKVDKRV ES

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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

Startup modelType of model: NONE
Final reconstructionApplied symmetry - Point group: C1 (asymmetric) / Resolution.type: BY AUTHOR / Resolution: 2.93 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 568328
Initial angle assignmentType: RANDOM ASSIGNMENT
Final angle assignmentType: MAXIMUM LIKELIHOOD

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