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- EMDB-21646: IL-23 receptor complex -

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Basic information

Entry
Database: EMDB / ID: EMD-21646
TitleIL-23 receptor complex
Map data
SampleIL-23 receptor extracellular domain complex:
(Interleukin-23 ...Interleukin 23) x 2 / (Interleukin-12 ...Interleukin 12) x 2
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 8 Å
AuthorsGlassman CR / Mathiharan YK / Panova O / Skiniotis G / Garcia KC
Funding support United States, 1 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)5R37AI051321 United States
CitationJournal: Cell / Year: 2021
Title: Structural basis for IL-12 and IL-23 receptor sharing reveals a gateway for shaping actions on T versus NK cells.
Authors: Caleb R Glassman / Yamuna Kalyani Mathiharan / Kevin M Jude / Leon Su / Ouliana Panova / Patrick J Lupardus / Jamie B Spangler / Lauren K Ely / Christoph Thomas / Georgios Skiniotis / K Christopher Garcia /
Abstract: Interleukin-12 (IL-12) and IL-23 are heterodimeric cytokines that are produced by antigen-presenting cells to regulate the activation and differentiation of lymphocytes, and they share IL-12Rβ1 as a ...Interleukin-12 (IL-12) and IL-23 are heterodimeric cytokines that are produced by antigen-presenting cells to regulate the activation and differentiation of lymphocytes, and they share IL-12Rβ1 as a receptor signaling subunit. We present a crystal structure of the quaternary IL-23 (IL-23p19/p40)/IL-23R/IL-12Rβ1 complex, together with cryoelectron microscopy (cryo-EM) maps of the complete IL-12 (IL-12p35/p40)/IL-12Rβ2/IL-12Rβ1 and IL-23 receptor (IL-23R) complexes, which reveal "non-canonical" topologies where IL-12Rβ1 directly engages the common p40 subunit. We targeted the shared IL-12Rβ1/p40 interface to design a panel of IL-12 partial agonists that preserved interferon gamma (IFNγ) induction by CD8 T cells but impaired cytokine production from natural killer (NK) cells in vitro. These cell-biased properties were recapitulated in vivo, where IL-12 partial agonists elicited anti-tumor immunity to MC-38 murine adenocarcinoma absent the NK-cell-mediated toxicity seen with wild-type IL-12. Thus, the structural mechanism of receptor sharing used by IL-12 family cytokines provides a protein interface blueprint for tuning this cytokine axis for therapeutics.
Validation ReportSummary, Full report, XML, About validation report
History
DepositionApr 1, 2020-
Header (metadata) releaseFeb 24, 2021-
Map releaseFeb 24, 2021-
UpdateMar 3, 2021-
Current statusMar 3, 2021Processing site: RCSB / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.0234
  • Imaged by UCSF Chimera
  • Download
  • Surface view colored by radius
  • Surface level: 0.0234
  • Imaged by UCSF Chimera
  • Download
Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

Downloads & links

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Map

FileDownload / File: emd_21646.map.gz / Format: CCP4 / Size: 15.6 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.7 Å/pix.
x 160 pix.
= 272. Å
1.7 Å/pix.
x 160 pix.
= 272. Å
1.7 Å/pix.
x 160 pix.
= 272. Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.7 Å
Density
Contour LevelBy AUTHOR: 0.0234 / Movie #1: 0.0234
Minimum - Maximum-0.020516817 - 0.08236688
Average (Standard dev.)0.00010288022 (±0.003430682)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions160160160
Spacing160160160
CellA=B=C: 272.0 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.71.71.7
M x/y/z160160160
origin x/y/z0.0000.0000.000
length x/y/z272.000272.000272.000
α/β/γ90.00090.00090.000
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS160160160
D min/max/mean-0.0210.0820.000

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Supplemental data

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Sample components

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Entire IL-23 receptor extracellular domain complex

EntireName: IL-23 receptor extracellular domain complex
Details: IL-23 (IL-23p19,p40), IL-12Rb1 (with affinity enhancing Y109S and Q132L mutations), IL-23R
Number of components: 5

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Component #1: protein, IL-23 receptor extracellular domain complex

ProteinName: IL-23 receptor extracellular domain complex
Details: IL-23 (IL-23p19,p40), IL-12Rb1 (with affinity enhancing Y109S and Q132L mutations), IL-23R
Recombinant expression: No
MassTheoretical: 153 MDa
SourceSpecies: Homo sapiens (human)
Source (engineered)Expression System: Trichoplusia ni (cabbage looper)

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Component #2: protein, Interleukin-23 receptor

ProteinName: Interleukin-23 receptor
Details: hIL-23R (25-309), 3C protease site, Protein C tag, 8xHis
Recombinant expression: No
SourceSpecies: Homo sapiens (human)
Source (engineered)Expression System: Homo sapiens (human)

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Component #3: protein, Interleukin-23 subunit alpha

ProteinName: Interleukin-23 subunit alphaInterleukin 23 / Details: IL23A (28-189) / Recombinant expression: No
SourceSpecies: Homo sapiens (human)
Source (engineered)Expression System: Trichoplusia ni (cabbage looper)

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Component #4: protein, Interleukin-12 subunit beta

ProteinName: Interleukin-12 subunit beta / Details: IL12B (23-328), Biotin Acceptor Peptide, 6xHis / Recombinant expression: No
SourceSpecies: Homo sapiens (human)
Source (engineered)Expression System: Trichoplusia ni (cabbage looper)

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Component #5: protein, Interleukin-12 receptor subunit beta-1

ProteinName: Interleukin-12 receptor subunit beta-1 / Details: IL12RB1 (25-542) Y109S Q132L, 6xHis / Recombinant expression: No
SourceSpecies: Homo sapiens (human)
Source (engineered)Expression System: Trichoplusia ni (cabbage looper)

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Experimental details

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Sample preparation

SpecimenSpecimen state: Particle / Method: cryo EM
Sample solutionSpecimen conc.: 1.04 mg/mL / pH: 7.4
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Temperature: 293 K / Humidity: 100 %

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
ImagingMicroscope: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Electron dose: 44 e/Å2 / Illumination mode: FLOOD BEAM
LensCs: 2.7 mm / Imaging mode: BRIGHT FIELD / Defocus: 1500.0 - 2400.0 nm
Specimen HolderModel: FEI TITAN KRIOS AUTOGRID HOLDER
CameraDetector: OTHER

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Image processing

ProcessingMethod: single particle reconstruction / Applied symmetry: C1 (asymmetric) / Number of projections: 33138
3D reconstructionSoftware: RELION / Resolution: 8 Å / Resolution method: FSC 0.143 CUT-OFF
FSC plot (resolution estimation)

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