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- EMDB-28278: Hexameric IL-21 complex with IL-21R and IL-2Rg -

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Basic information

Entry
Database: EMDB / ID: EMD-28278
TitleHexameric IL-21 complex with IL-21R and IL-2Rg
Map datasharpened map
Sample
  • Complex: Hexameric IL-21 complex with IL-21R and IL-2Rg
    • Complex: Interleukin-21
      • Protein or peptide: Interleukin-21
    • Complex: Interleukin-21 receptor
      • Protein or peptide: Interleukin-21 receptor
    • Complex: Cytokine receptor common subunit gamma
      • Protein or peptide: Cytokine receptor common subunit gamma
KeywordsIL-21 / receptor / complex / signaling / CYTOKINE
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.7 Å
AuthorsAbhiraman GC / Jude KM / Caveney NA / Garcia KC
Funding support United States, 2 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)RO1-AI51321 United States
Bill & Melinda Gates Foundation United States
CitationJournal: Cell Rep / Year: 2023
Title: A structural blueprint for interleukin-21 signal modulation.
Authors: Gita C Abhiraman / Theodora U J Bruun / Nathanael A Caveney / Leon L Su / Robert A Saxton / Qian Yin / Shaogeng Tang / Mark M Davis / Kevin M Jude / K Christopher Garcia /
Abstract: Interleukin-21 (IL-21) plays a critical role in generating immunological memory by promoting the germinal center reaction, yet clinical use of IL-21 remains challenging because of its pleiotropy and ...Interleukin-21 (IL-21) plays a critical role in generating immunological memory by promoting the germinal center reaction, yet clinical use of IL-21 remains challenging because of its pleiotropy and association with autoimmune disease. To better understand the structural basis of IL-21 signaling, we determine the structure of the IL-21-IL-21R-γc ternary signaling complex by X-ray crystallography and a structure of a dimer of trimeric complexes using cryo-electron microscopy. Guided by the structure, we design analogs of IL-21 by introducing substitutions to the IL-21-γc interface. These IL-21 analogs act as partial agonists that modulate downstream activation of pS6, pSTAT3, and pSTAT1. These analogs exhibit differential activity on T and B cell subsets and modulate antibody production in human tonsil organoids. These results clarify the structural basis of IL-21 signaling and offer a potential strategy for tunable manipulation of humoral immunity.
History
DepositionSep 30, 2022-
Header (metadata) releaseJun 28, 2023-
Map releaseJun 28, 2023-
UpdateJun 28, 2023-
Current statusJun 28, 2023Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_28278.png

Downloads & links

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Map

FileDownload / File: emd_28278.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Annotationsharpened map
Voxel sizeX=Y=Z: 1.151 Å
Density
Contour LevelBy AUTHOR: 0.14
Minimum - Maximum-0.09090652 - 2.1924708
Average (Standard dev.)0.0006294099 (±0.021631746)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 294.656 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_28278_msk_1.map
Projections & Slices
AxesZYX

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Half map: half map A

Fileemd_28278_half_map_1.map
Annotationhalf map A
Projections & Slices
AxesZYX

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Histogram

Histogram (log scale)

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Half map: half map B

Fileemd_28278_half_map_2.map
Annotationhalf map B
Projections & Slices
AxesZYX

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Sample components

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Entire : Hexameric IL-21 complex with IL-21R and IL-2Rg

EntireName: Hexameric IL-21 complex with IL-21R and IL-2Rg
Components
  • Complex: Hexameric IL-21 complex with IL-21R and IL-2Rg
    • Complex: Interleukin-21
      • Protein or peptide: Interleukin-21
    • Complex: Interleukin-21 receptor
      • Protein or peptide: Interleukin-21 receptor
    • Complex: Cytokine receptor common subunit gamma
      • Protein or peptide: Cytokine receptor common subunit gamma

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Supramolecule #1: Hexameric IL-21 complex with IL-21R and IL-2Rg

SupramoleculeName: Hexameric IL-21 complex with IL-21R and IL-2Rg / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all

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Supramolecule #2: Interleukin-21

SupramoleculeName: Interleukin-21 / type: complex / ID: 2 / Parent: 1 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)

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Supramolecule #3: Interleukin-21 receptor

SupramoleculeName: Interleukin-21 receptor / type: complex / ID: 3 / Parent: 1 / Macromolecule list: #2
Source (natural)Organism: Homo sapiens (human)

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Supramolecule #4: Cytokine receptor common subunit gamma

SupramoleculeName: Cytokine receptor common subunit gamma / type: complex / ID: 4 / Parent: 1 / Macromolecule list: #3
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Interleukin-21

MacromoleculeName: Interleukin-21 / type: protein_or_peptide / ID: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString:
QGQDRHMIRM RQLIDIVDQL KNYVNDLVPE FLPAPEDVET NCEWSAFSCF QKAQLKSANT GNNERIIQVS IKKLKRKPPS TNAGRRQKHR LTCPSCDSYE KKPPKEFLER FKSLLQKMIH QHLSSRTHGS EDSGAPGSHH HHHH

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Macromolecule #2: Interleukin-21 receptor

MacromoleculeName: Interleukin-21 receptor / type: protein_or_peptide / ID: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Recombinant expressionOrganism: Trichoplusia ni (cabbage looper)
SequenceString: CPDLVCYTDY LQTVICILEM WNLHPSTLTL TWQDQYEELK DEATSCSLHR SAHNATHATY TCHMDVFHFM ADDIFSVQIT DQSGQYSQEC GSFLLAESIK PAPPFDVTVT FSGQYQISWR SDYEDPAFYM LKGKLQYELQ YRNRGDPWAV SPRRKLISVD SRSVSLLPLE ...String:
CPDLVCYTDY LQTVICILEM WNLHPSTLTL TWQDQYEELK DEATSCSLHR SAHNATHATY TCHMDVFHFM ADDIFSVQIT DQSGQYSQEC GSFLLAESIK PAPPFDVTVT FSGQYQISWR SDYEDPAFYM LKGKLQYELQ YRNRGDPWAV SPRRKLISVD SRSVSLLPLE FRKDSSYELQ VRAGPMPGSS YQGTWSEWSD PVIFQTQSEE KAASGRGLND IFEAQKIEWH EHHHHHH

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Macromolecule #3: Cytokine receptor common subunit gamma

MacromoleculeName: Cytokine receptor common subunit gamma / type: protein_or_peptide / ID: 3 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Recombinant expressionOrganism: Trichoplusia ni (cabbage looper)
SequenceString: PLPLPEVQCF VFNVEYMNCT WQSSSEPQPT NLTLHYWYKN SDNDKVQKCS HYLFSEEITS GCQLQKKEIH LYQTFVVQLQ DPREPRRQAT QMLKLQNLVI PWAPENLTLH KLSESQLELN WNNRFLNHCL EHLVQYRTDW DHSWTEQSVD YRHKFSLPSV DGQKRYTFRV ...String:
PLPLPEVQCF VFNVEYMNCT WQSSSEPQPT NLTLHYWYKN SDNDKVQKCS HYLFSEEITS GCQLQKKEIH LYQTFVVQLQ DPREPRRQAT QMLKLQNLVI PWAPENLTLH KLSESQLELN WNNRFLNHCL EHLVQYRTDW DHSWTEQSVD YRHKFSLPSV DGQKRYTFRV RSRFNPLCGS AQHWSEWSHP IHWGSNTSKE NHHHHHH

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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

Concentration3 mg/mL
BufferpH: 7.2
GridModel: Quantifoil R1.2/1.3 / Material: GOLD / Mesh: 200
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeTFS GLACIOS
Electron beamAcceleration voltage: 200 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: OTHER / Imaging mode: OTHER / Nominal defocus max: 2.5 µm / Nominal defocus min: 1.0 µm
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average exposure time: 5.0 sec. / Average electron dose: 49.0 e/Å2

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Image processing

Startup modelType of model: OTHER / Details: Ab initio
Initial angle assignmentType: OTHER
Final angle assignmentType: OTHER
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.7 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC (ver. 3.3.2) / Number images used: 57295
FSC plot (resolution estimation)

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