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- EMDB-44791: Structure of the IFN-lambda3/IFN-lambdaR1/IL-10Rbeta receptor com... -

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Basic information

Entry
Database: EMDB / ID: EMD-44791
TitleStructure of the IFN-lambda3/IFN-lambdaR1/IL-10Rbeta receptor complex with an engineered IL-10Rbeta
Map data
Sample
  • Complex: Structure of the IFN-lambda3/IFN-lambdaR1/IL-10Rbeta receptor complex with an engineered IL-10Rbeta
    • Protein or peptide: Interleukin-10 receptor subunit beta
    • Protein or peptide: Interferon lambda receptor 1
    • Protein or peptide: Interferon lambda-3
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
KeywordsINTERFERON / CYTOKINE / CYTOKINE RECEPTOR / TYPE III INTERFERON
Function / homology
Function and homology information


interleukin-10 receptor activity / response to type III interferon / interleukin-28 receptor complex / mucosal immune response / positive regulation of cellular respiration / type III interferon-mediated signaling pathway / interleukin-10-mediated signaling pathway / regulation of defense response to virus by host / cytokine receptor activity / Other interleukin signaling ...interleukin-10 receptor activity / response to type III interferon / interleukin-28 receptor complex / mucosal immune response / positive regulation of cellular respiration / type III interferon-mediated signaling pathway / interleukin-10-mediated signaling pathway / regulation of defense response to virus by host / cytokine receptor activity / Other interleukin signaling / negative regulation of viral genome replication / Interleukin-20 family signaling / Interleukin-10 signaling / cell surface receptor signaling pathway via JAK-STAT / coreceptor activity / cytokine activity / positive regulation of receptor signaling pathway via JAK-STAT / cytokine-mediated signaling pathway / cellular response to virus / positive regulation of immune response / signaling receptor activity / defense response to virus / immune response / inflammatory response / signaling receptor binding / negative regulation of cell population proliferation / innate immune response / signal transduction / extracellular space / extracellular region / membrane / plasma membrane
Similarity search - Function
Interferon lambda / Interferon lambda superfamily / Interleukin-28A / Interferon/interleukin receptor domain / Interferon-alpha/beta receptor, fibronectin type III / : / Tissue factor / Fibronectin type-III domain profile. / Fibronectin type III / Fibronectin type III superfamily / Immunoglobulin-like fold
Similarity search - Domain/homology
Interleukin-10 receptor subunit beta / Interferon lambda receptor 1 / Interferon lambda-3
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.0 Å
AuthorsZhang B / Grubbe WS / Mendoza JL / Zhao M
Funding support United States, 2 items
OrganizationGrant numberCountry
Howard Hughes Medical Institute (HHMI) United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)1R35GM147179-01 United States
CitationJournal: Nat Commun / Year: 2025
Title: Structural studies of the IFNλ4 receptor complex using cryoEM enabled by protein engineering.
Authors: William S Grubbe / Bixia Zhang / Aileen Kauffman / Fabian Byléhn / Kasia Padoł / Hae-Gwang Jung / Seung Bum Park / Jessica M Priest / Engin Özkan / Juan J de Pablo / T Jake Liang / ...Authors: William S Grubbe / Bixia Zhang / Aileen Kauffman / Fabian Byléhn / Kasia Padoł / Hae-Gwang Jung / Seung Bum Park / Jessica M Priest / Engin Özkan / Juan J de Pablo / T Jake Liang / Minglei Zhao / Juan L Mendoza /
Abstract: IFNλ4 has posed a conundrum in human immunology since its discovery in 2013, with its expression linked to complications with viral clearance. While genetic and cellular studies revealed the ...IFNλ4 has posed a conundrum in human immunology since its discovery in 2013, with its expression linked to complications with viral clearance. While genetic and cellular studies revealed the detrimental effects of IFNλ4 expression, extensive structural and functional characterization has been limited by the inability to express and purify the protein, complicating explanations of its paradoxical behavior. In this work, we report a method for robust production of IFNλ4. We then use yeast surface display to affinity-mature IL10Rβ and solve the 72 kilodalton structures of IFNλ4 (3.26 Å) and IFNλ3 (3.00 Å) in complex with their receptors IFNλR1 and IL10Rβ using cryogenic electron microscopy. Comparison of the structures highlights differences in receptor engagement and reveals a distinct 12-degree rotation in overall receptor geometry, providing a potential mechanistic explanation for differences in cell signaling, downstream gene induction, and antiviral activities. Further, we perform a structural analysis using molecular modeling and simulation to identify a unique region of IFNλ4 that, when replaced, enables secretion of the protein from cells. These findings provide a structural and functional understanding of the IFNλ4 protein and enable future comprehensive studies towards correcting IFNλ4 dysfunction in large populations of affected patients.
History
DepositionMay 8, 2024-
Header (metadata) releaseJan 29, 2025-
Map releaseJan 29, 2025-
UpdateFeb 5, 2025-
Current statusFeb 5, 2025Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_44791.png

Downloads & links

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Map

FileDownload / File: emd_44791.map.gz / Format: CCP4 / Size: 40.6 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.07 Å/pix.
x 220 pix.
= 234.3 Å		1.07 Å/pix.
x 220 pix.
= 234.3 Å		1.07 Å/pix.
x 220 pix.
= 234.3 Å

Surface

Projections

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Images are generated by Spider.

Voxel sizeX=Y=Z: 1.065 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.018
Minimum - Maximum-0.08634206 - 0.1494476
Average (Standard dev.)0.0000204848 (±0.0033335958)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions220220220
Spacing220220220
CellA=B=C: 234.30002 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_44791_half_map_1.map
Projections & Slices
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Slices (1/2)
Density Histograms

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Histogram (log scale)

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Half map: #1

Fileemd_44791_half_map_2.map
Projections & Slices
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Sample components

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Entire : Structure of the IFN-lambda3/IFN-lambdaR1/IL-10Rbeta receptor com...

EntireName: Structure of the IFN-lambda3/IFN-lambdaR1/IL-10Rbeta receptor complex with an engineered IL-10Rbeta
Components
  • Complex: Structure of the IFN-lambda3/IFN-lambdaR1/IL-10Rbeta receptor complex with an engineered IL-10Rbeta
    • Protein or peptide: Interleukin-10 receptor subunit beta
    • Protein or peptide: Interferon lambda receptor 1
    • Protein or peptide: Interferon lambda-3
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose

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Supramolecule #1: Structure of the IFN-lambda3/IFN-lambdaR1/IL-10Rbeta receptor com...

SupramoleculeName: Structure of the IFN-lambda3/IFN-lambdaR1/IL-10Rbeta receptor complex with an engineered IL-10Rbeta
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#3
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 71.742 KDa

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Macromolecule #1: Interleukin-10 receptor subunit beta

MacromoleculeName: Interleukin-10 receptor subunit beta / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 24.773643 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: GSMVPPPENV RMNSVNFKNI LQWESPAFAK GQLTFTAQYL SYRIFQDKCM QTTLTECDFS SLSKYGDHTL RVRAEFADEH SDWVQITFC PVDDTIIGPP GMQVEVLADS LHMRFLAPKI ENEYETWTMK DMYNSWTYNV QYWKQGTDEK FQITPQYDFE V LRNLEPRT ...String:
GSMVPPPENV RMNSVNFKNI LQWESPAFAK GQLTFTAQYL SYRIFQDKCM QTTLTECDFS SLSKYGDHTL RVRAEFADEH SDWVQITFC PVDDTIIGPP GMQVEVLADS LHMRFLAPKI ENEYETWTMK DMYNSWTYNV QYWKQGTDEK FQITPQYDFE V LRNLEPRT TYCVQVRGFL PDRNKAGEWS EPVCEQTTHD ETVPSAAAHH HHHH

UniProtKB: Interleukin-10 receptor subunit beta

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Macromolecule #2: Interferon lambda receptor 1

MacromoleculeName: Interferon lambda receptor 1 / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 23.628096 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: RPRLAPPQNV TLLSQNFSVY LTWLPGLGNP QDVTYFVAYQ SSPTRRRWRE VEECAGTKEL LCSMMCLKKQ DLYNKFKGRV RTVSPSSKS PWVESEYLDY LFEVEPAPPV LVLTQTEEIL SANATYQLPP CMPPLDLKYE VAFWKEGAGN KTLFPVTPHG Q PVQITLQP ...String:
RPRLAPPQNV TLLSQNFSVY LTWLPGLGNP QDVTYFVAYQ SSPTRRRWRE VEECAGTKEL LCSMMCLKKQ DLYNKFKGRV RTVSPSSKS PWVESEYLDY LFEVEPAPPV LVLTQTEEIL SANATYQLPP CMPPLDLKYE VAFWKEGAGN KTLFPVTPHG Q PVQITLQP AASEHHCLSA RTIYTFSVPK YSKFSKPTCF LLEVPEANAA A

UniProtKB: Interferon lambda receptor 1

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Macromolecule #3: Interferon lambda-3

MacromoleculeName: Interferon lambda-3 / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 19.877871 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString:
GSARGCHIAQ FKSLSPQELQ AFKRAKDALE ESLLLKDCKC RSRLFPRTWD LRQLQVRERP VALEAELALT LKVLEATADT DPALGDVLD QPLHTLHHIL SQLRACIQPQ PTAGPRTRGR LHHWLHRLQE APKKESPGCL EASVTFNLFR LLTRDLNCVA S GDLCVAAA HHHHHHHH

UniProtKB: Interferon lambda-3

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Macromolecule #4: 2-acetamido-2-deoxy-beta-D-glucopyranose

MacromoleculeName: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 4 / Number of copies: 2 / 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 state2D array

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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: 60.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.5 µm / Nominal defocus min: 0.9 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: INSILICO MODEL
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.0 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 205839
Initial angle assignmentType: RANDOM ASSIGNMENT
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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