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- PDB-10nd: Cryo-EM structure of human IL-10RA in complex with VHH E07 -

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Basic information

Entry
Database: PDB / ID: 10nd
TitleCryo-EM structure of human IL-10RA in complex with VHH E07
Components
  • Interleukin-10 receptor subunit alpha
  • VHH antibody E07
KeywordsIMMUNE SYSTEM / Complex
Function / homology
Function and homology information


interleukin-10 binding / interleukin-10 receptor activity / interleukin-10 receptor complex / ubiquitin-dependent endocytosis / interleukin-10-mediated signaling pathway / intestinal epithelial structure maintenance / positive regulation of tyrosine phosphorylation of STAT protein / Interleukin-10 signaling / regulation of synapse organization / cell surface receptor signaling pathway via JAK-STAT ...interleukin-10 binding / interleukin-10 receptor activity / interleukin-10 receptor complex / ubiquitin-dependent endocytosis / interleukin-10-mediated signaling pathway / intestinal epithelial structure maintenance / positive regulation of tyrosine phosphorylation of STAT protein / Interleukin-10 signaling / regulation of synapse organization / cell surface receptor signaling pathway via JAK-STAT / Nuclear events stimulated by ALK signaling in cancer / negative regulation of autophagy / positive regulation of receptor signaling pathway via JAK-STAT / negative regulation of inflammatory response / cytokine-mediated signaling pathway / signaling receptor activity / response to lipopolysaccharide / apical plasma membrane / positive regulation of cell population proliferation / plasma membrane / cytosol / cytoplasm
Similarity search - Function
Tissue factor / Fibronectin type III / Fibronectin type III superfamily / Immunoglobulin-like fold
Similarity search - Domain/homology
Interleukin-10 receptor subunit alpha
Similarity search - Component
Biological speciesHomo sapiens (human)
Lama glama (llama)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.4 Å
AuthorsXu, H.
Funding support1items
OrganizationGrant numberCountry
Other private
CitationJournal: Nature / Year: 2026
Title: Engineered TYK2 dependence enables myeloid-selective IL-10 receptor agonism.
Authors: D Alejandro Canaria / Trang T T Nguyen / Huang Huang / Hui Xu / Lili Yue / Yongyao Fu / Hoa Truong / Kerul Patel / Weimei Xing / Jayamary Divya Ravichandar / Cong Xing / Aron L Martin / ...Authors: D Alejandro Canaria / Trang T T Nguyen / Huang Huang / Hui Xu / Lili Yue / Yongyao Fu / Hoa Truong / Kerul Patel / Weimei Xing / Jayamary Divya Ravichandar / Cong Xing / Aron L Martin / George Delidakis / Sylvia Wong / Andrew Pae / Yu Yu / Ramsay Macdonald / Zhiyu Huang / Meagan C Main / Amanali Rodriguez / Xiaoli Lin / Maria L Mouchess / Magdeleine Hung / Ellen M McGlinchey / Lei Chen / Nicole Schirle Oakdale / Brian Carr / Megan L Koleske / Chingwei V Lee / Chen Chen / Tangsheng Yi /
Abstract: Interleukin-10 (IL-10) is a central anti-inflammatory cytokine that suppresses immune responses in myeloid cells but can also activate T cells, limiting its therapeutic use in chronic inflammatory ...Interleukin-10 (IL-10) is a central anti-inflammatory cytokine that suppresses immune responses in myeloid cells but can also activate T cells, limiting its therapeutic use in chronic inflammatory diseases owing to narrow efficacy windows and dose-limiting toxicities. Here we show that myeloid and T cells differ in their dependence on JAK-family kinase pairing for IL-10 signalling and function. We took advantage of this differential kinase dependence to engineer a tetravalent nanobody-based myeloid-selective IL-10 receptor agonist (msIL-10R agonist) that fully recapitulates IL-10's potent suppression of monocytes, macrophages and dendritic cells while avoiding stimulation of T cells. Cryo-electron microscopy structural analysis reveals a distinct receptor cross-linking geometry of the msIL-10R agonist compared with native IL-10 family cytokines. This tetravalent architecture renders signalling strictly TYK2-dependent and highly sensitive to IL-10Rα and IL-10Rβ receptor abundance, thereby conferring selective activity in myeloid cells. This msIL-10R agonist reduces inflammation in humanized mouse models of lipopolysaccharide challenge, delayed-type hypersensitivity and colitis. A humanized version exhibits IgG-like pharmacokinetics, sustained receptor occupancy and durable myeloid suppression up to 30 days without T cell activation or haematological toxicities in non-human primates. These findings establish a geometry-based strategy for achieving cell-type-selective cytokine signalling and identify the msIL-10R agonist as a therapeutic candidate for myeloid-driven inflammatory diseases, including inflammatory bowel diseases.
History
DepositionJan 28, 2026Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 21, 2026Provider: repository / Type: Initial release
Revision 1.0Oct 21, 2026Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.1Oct 28, 2026Group: Data collection / Database references / Category: citation / citation_author / em_admin
Item: _citation.pdbx_database_id_PubMed / _citation.title / _em_admin.last_update
Revision 1.1Oct 28, 2026Data content type: EM metadata / Data content type: EM metadata / EM metadata / Group: Database references / Experimental summary / Data content type: EM metadata / EM metadata / EM metadata / Category: citation / citation_author / em_admin / Data content type: EM metadata / EM metadata / EM metadata
Item: _citation.pdbx_database_id_PubMed / _citation.title / _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 alpha
B: VHH antibody E07


Theoretical massNumber of molelcules
Total (without water)40,5202
Polymers40,5202
Non-polymers00
Water43224
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 alpha / IL-10 receptor subunit alpha / IL-10R subunit alpha / IL-10RA / CDw210a / Interleukin-10 receptor ...IL-10 receptor subunit alpha / IL-10R subunit alpha / IL-10RA / CDw210a / Interleukin-10 receptor subunit 1 / IL-10R subunit 1 / IL-10R1


Mass: 25842.850 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: IL10RA, IL10R / Production host: Homo sapiens (human) / References: UniProt: Q13651
#2: Antibody VHH antibody E07


Mass: 14677.274 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Lama glama (llama) / Production host: Cricetulus griseus (Chinese hamster)
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 24 / Source method: isolated from a natural source / Formula: H2O
Has protein modificationY

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Experimental details

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Experiment

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

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Sample preparation

ComponentName: Complex of human IL-10RA with VHH E07 and anti-VHH Fab
Type: COMPLEX / Entity ID: #1-#2 / Source: RECOMBINANT
Molecular weightValue: 0.09 MDa / Experimental value: NO
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
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal magnification: 165000 X / Nominal defocus max: 2200 nm / Nominal defocus min: 600 nm
Image recordingElectron dose: 50 e/Å2 / Film or detector model: FEI FALCON IV (4k x 4k)

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Processing

EM software
IDNameVersionCategory
1cryoSPARCparticle selection
9PHENIX1.21.2_5419model refinement
13cryoSPARC3D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 2.4 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 458458 / Symmetry type: POINT
Atomic model buildingPDB-ID: 1y6k

1y6k


Pdb chain-ID: R / Accession code: 1y6k / Source name: PDB / Type: experimental model
RefinementCross valid method: NONE

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