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- PDB-9bpv: Structure of the IFN-lambda3/IFN-lambdaR1/IL-10Rbeta receptor com... -

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Basic information

Entry
Database: PDB / ID: 9bpv
TitleStructure of the IFN-lambda3/IFN-lambdaR1/IL-10Rbeta receptor complex with an engineered IL-10Rbeta
Components
  • Interferon lambda receptor 1
  • Interferon lambda-3
  • Interleukin-10 receptor subunit beta
KeywordsCYTOKINE / INTERFERON / 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 / Interleukin-20 family signaling / negative regulation of viral genome replication / 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 / positive regulation of immune response / cellular response to virus / 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)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3 Å
AuthorsZhang, B. / Grubbe, W.S. / Mendoza, J.L. / Zhao, M.
Funding support United States, 2items
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, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 29, 2025Provider: repository / Type: Initial release
Revision 1.1Feb 5, 2025Group: Data collection / Database references / Category: citation / citation_author / em_admin
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _em_admin.last_update

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Interleukin-10 receptor subunit beta
B: Interferon lambda receptor 1
C: Interferon lambda-3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)68,7225
Polymers68,2803
Non-polymers4422
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

#1: Protein Interleukin-10 receptor subunit beta / IL-10 receptor subunit beta / IL-10R subunit beta / IL-10RB / Cytokine receptor class-II member 4 / ...IL-10 receptor subunit beta / IL-10R subunit beta / IL-10RB / Cytokine receptor class-II member 4 / Cytokine receptor family 2 member 4 / CRF2-4 / Interleukin-10 receptor subunit 2 / IL-10R subunit 2 / IL-10R2


Mass: 24773.643 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: IL10RB, CRFB4, D21S58, D21S66 / Production host: Homo sapiens (human) / References: UniProt: Q08334
#2: Protein Interferon lambda receptor 1 / IFN-lambda receptor 1 / IFN-lambda-R1 / Cytokine receptor class-II member 12 / Cytokine receptor ...IFN-lambda receptor 1 / IFN-lambda-R1 / Cytokine receptor class-II member 12 / Cytokine receptor family 2 member 12 / CRF2-12 / Interleukin-28 receptor subunit alpha / IL-28 receptor subunit alpha / IL-28R-alpha / IL-28RA / Likely interleukin or cytokine receptor 2 / LICR2


Mass: 23628.096 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: IFNLR1, IL28RA, LICR2 / Production host: Homo sapiens (human) / References: UniProt: Q8IU57
#3: Protein Interferon lambda-3 / IFN-lambda-3 / Cytokine Zcyto22 / Interleukin-28B / IL-28B / Interleukin-28C / IL-28C


Mass: 19877.871 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: IFNL3, IL28B, IL28C, ZCYTO22 / Production host: Homo sapiens (human) / References: UniProt: Q8IZI9
#4: Sugar ChemComp-NAG / 2-acetamido-2-deoxy-beta-D-glucopyranose / N-acetyl-beta-D-glucosamine / 2-acetamido-2-deoxy-beta-D-glucose / 2-acetamido-2-deoxy-D-glucose / 2-acetamido-2-deoxy-glucose / N-ACETYL-D-GLUCOSAMINE


Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C8H15NO6
IdentifierTypeProgram
DGlcpNAcbCONDENSED IUPAC CARBOHYDRATE SYMBOLGMML 1.0
N-acetyl-b-D-glucopyranosamineCOMMON NAMEGMML 1.0
b-D-GlcpNAcIUPAC CARBOHYDRATE SYMBOLPDB-CARE 1.0
GlcNAcSNFG CARBOHYDRATE SYMBOLGMML 1.0
Has ligand of interestN
Has protein modificationY

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: 2D ARRAY / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: Structure of the IFN-lambda3/IFN-lambdaR1/IL-10Rbeta receptor complex with an engineered IL-10Rbeta
Type: COMPLEX / Entity ID: #1-#3 / Source: RECOMBINANT
Molecular weightValue: .071742 MDa / Experimental value: YES
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 7.5
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2500 nm / Nominal defocus min: 900 nm
Image recordingElectron dose: 60 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)

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Processing

EM softwareName: PHENIX / Version: 1.21.1_5286: / Category: model refinement
CTF correctionType: PHASE FLIPPING ONLY
3D reconstructionResolution: 3 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 205839 / Symmetry type: POINT

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