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- EMDB-75302: Cryo-EM structure of human IL-10RA and IL-10RB in complex with ta... -

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Basic information

Entry
Database: EMDB / ID: EMD-75302
TitleCryo-EM structure of human IL-10RA and IL-10RB in complex with tandem VHHs E07-A05
Map data
Sample
  • Complex: Complex of human IL-10RA, IL-10RB with tandem VHHs E07-A05 and anti-VHH Fab
    • Protein or peptide: Interleukin-10 receptor subunit alpha
    • Protein or peptide: tandem VHHs E07-A05
    • Protein or peptide: Interleukin-10 receptor subunit beta
    • Protein or peptide: Fab Heavy Chain
    • Protein or peptide: Fab Light Chain
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
Keywordscomplex / IMMUNE SYSTEM
Function / homology
Function and homology information


interleukin-10 binding / interleukin-10 receptor activity / interleukin-28 receptor complex / interleukin-10 receptor complex / type III interferon-mediated signaling pathway / ubiquitin-dependent endocytosis / positive regulation of cellular respiration / interleukin-10-mediated signaling pathway / intestinal epithelial structure maintenance / Other interleukin signaling ...interleukin-10 binding / interleukin-10 receptor activity / interleukin-28 receptor complex / interleukin-10 receptor complex / type III interferon-mediated signaling pathway / ubiquitin-dependent endocytosis / positive regulation of cellular respiration / interleukin-10-mediated signaling pathway / intestinal epithelial structure maintenance / Other interleukin signaling / Interleukin-20 family signaling / positive regulation of tyrosine phosphorylation of STAT protein / Interleukin-10 signaling / regulation of synapse organization / acute-phase response / cell surface receptor signaling pathway via JAK-STAT / coreceptor activity / Nuclear events stimulated by ALK signaling in cancer / negative regulation of autophagy / positive regulation of receptor signaling pathway via JAK-STAT / cellular response to virus / negative regulation of inflammatory response / cytokine-mediated signaling pathway / signaling receptor activity / response to lipopolysaccharide / inflammatory response / signaling receptor complex / apical plasma membrane / immune response / positive regulation of cell population proliferation / signal transduction / membrane / plasma membrane / cytosol / cytoplasm
Similarity search - Function
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 / Interleukin-10 receptor subunit alpha
Similarity search - Component
Biological speciesHomo sapiens (human) / synthetic construct (others)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.14 Å
AuthorsXu H
Funding support1 items
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, 2026-
Header (metadata) releaseOct 21, 2026-
Map releaseOct 21, 2026-
UpdateOct 28, 2026-
Current statusOct 28, 2026Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_75302.png

Downloads & links

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Map

FileDownload / File: emd_75302.map.gz / Format: CCP4 / Size: 421.9 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.73 Å/pix.
x 480 pix.
= 349.92 Å		0.73 Å/pix.
x 480 pix.
= 349.92 Å		0.73 Å/pix.
x 480 pix.
= 349.92 Å

Surface

Projections

Slices (1/3)

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.729 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.075
Minimum - Maximum-0.35622525 - 0.6408581
Average (Standard dev.)-0.00003751061 (±0.0088693965)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions480480480
Spacing480480480
CellA=B=C: 349.91998 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_75302_msk_1.map
Projections & Slices
AxesZYX

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Density Histograms

Histogram

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Half map: #2

Fileemd_75302_half_map_1.map
Projections & Slices
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Histogram

Histogram (log scale)

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Half map: #1

Fileemd_75302_half_map_2.map
Projections & Slices
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Sample components

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Entire : Complex of human IL-10RA, IL-10RB with tandem VHHs E07-A05 and an...

EntireName: Complex of human IL-10RA, IL-10RB with tandem VHHs E07-A05 and anti-VHH Fab
Components
  • Complex: Complex of human IL-10RA, IL-10RB with tandem VHHs E07-A05 and anti-VHH Fab
    • Protein or peptide: Interleukin-10 receptor subunit alpha
    • Protein or peptide: tandem VHHs E07-A05
    • Protein or peptide: Interleukin-10 receptor subunit beta
    • Protein or peptide: Fab Heavy Chain
    • Protein or peptide: Fab Light Chain
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose

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Supramolecule #1: Complex of human IL-10RA, IL-10RB with tandem VHHs E07-A05 and an...

SupramoleculeName: Complex of human IL-10RA, IL-10RB with tandem VHHs E07-A05 and anti-VHH Fab
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#5
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 127 KDa

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Macromolecule #1: Interleukin-10 receptor subunit alpha

MacromoleculeName: Interleukin-10 receptor subunit alpha / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 25.84285 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: HGTELPSPPS VWFEAEFFHH ILHWTPIPNQ SESTCYEVAL LRYGIESWNS ISNCSQTLSY DLTAVTLDLY HSNGYRARVR AVDGSRHSN WTVTNTRFSV DEVTLTVGSV NLEIHNGFIL GKIQLPRPKM APANDTYESI FSHFREYEIA IRKVPGNFTF T HKKVKHEN ...String:
HGTELPSPPS VWFEAEFFHH ILHWTPIPNQ SESTCYEVAL LRYGIESWNS ISNCSQTLSY DLTAVTLDLY HSNGYRARVR AVDGSRHSN WTVTNTRFSV DEVTLTVGSV NLEIHNGFIL GKIQLPRPKM APANDTYESI FSHFREYEIA IRKVPGNFTF T HKKVKHEN FSLLTSGEVG EFCVQVKPSV ASRSNKGMWS KEECISLTRQ YFTVTNGGGG SHHHHHHHH

UniProtKB: Interleukin-10 receptor subunit alpha

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Macromolecule #2: tandem VHHs E07-A05

MacromoleculeName: tandem VHHs E07-A05 / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: synthetic construct (others)
Molecular weightTheoretical: 27.797807 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: ELQLVESGGG LVQPGGSLRL SCAASGRTFS AYGMGWFRQA PGKGREFVAA IRWIGDSTYY ADSVKGRFTI SKDNSKNTLY LQMNSLRPE DTAVYYCAAK TSVTSYLSEK SYNYWGKGTP VTVSSGGGSE VQLVESGGGL VQPGGSLRLS CAASGNSLDY P TIGWFRQA ...String:
ELQLVESGGG LVQPGGSLRL SCAASGRTFS AYGMGWFRQA PGKGREFVAA IRWIGDSTYY ADSVKGRFTI SKDNSKNTLY LQMNSLRPE DTAVYYCAAK TSVTSYLSEK SYNYWGKGTP VTVSSGGGSE VQLVESGGGL VQPGGSLRLS CAASGNSLDY P TIGWFRQA PGKGREGVSC ISASDGSTHY ADSVKGRFTI SRDNSKNTLY LQMNSLRPED TAVYYCAASL WGLGCKSEAD YD YWGKGTP VTVSSHHHHH H

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Macromolecule #3: Interleukin-10 receptor subunit beta

MacromoleculeName: Interleukin-10 receptor subunit beta / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 24.947713 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MVPPPENVRM NSVNFKNILQ WESPAFAKGN LTFTAQYLSY RIFQDKCMNT TLTECDFSSL SKYGDHTLRV RAEFADEHSD WVNITFCPV DDTIIGPPGM QVEVLADSLH MRFLAPKIEN EYETWTMKNV YNSWTYNVQY WKNGTDEKFQ ITPQYDFEVL R NLEPWTTY ...String:
MVPPPENVRM NSVNFKNILQ WESPAFAKGN LTFTAQYLSY RIFQDKCMNT TLTECDFSSL SKYGDHTLRV RAEFADEHSD WVNITFCPV DDTIIGPPGM QVEVLADSLH MRFLAPKIEN EYETWTMKNV YNSWTYNVQY WKNGTDEKFQ ITPQYDFEVL R NLEPWTTY CVQVRGFLPD RNKAGEWSEP VCEQTTHDET VPSGGGGSHH HHHHHH

UniProtKB: Interleukin-10 receptor subunit beta

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Macromolecule #4: Fab Heavy Chain

MacromoleculeName: Fab Heavy Chain / type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: synthetic construct (others)
Molecular weightTheoretical: 25.684463 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: EISEVQLVES GGGLVQPGGS LRLSCAASGF NFSYYSIHWV RQAPGKGLEW VAYISSSSSY TSYADSVKGR FTISADTSKN TAYLQMNSL RAEDTAVYYC ARGYQYWQYH ASWYWNGGLD YWGQGTLVTV SSASTKGPSV FPLAPSSKST SGGTAALGCL V KDYFPEPV ...String:
EISEVQLVES GGGLVQPGGS LRLSCAASGF NFSYYSIHWV RQAPGKGLEW VAYISSSSSY TSYADSVKGR FTISADTSKN TAYLQMNSL RAEDTAVYYC ARGYQYWQYH ASWYWNGGLD YWGQGTLVTV SSASTKGPSV FPLAPSSKST SGGTAALGCL V KDYFPEPV TVSWNSGALT SGVHTFPAVL QSSGLYSLSS VVTVPSSSLG TQTYICNVNH KPSNTKVDKK VEPKSCDKTH T

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Macromolecule #5: Fab Light Chain

MacromoleculeName: Fab Light Chain / type: protein_or_peptide / ID: 5 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: synthetic construct (others)
Molecular weightTheoretical: 23.258783 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: SDIQMTQSPS SLSASVGDRV TITCRASQSV SSAVAWYQQK PGKAPKLLIY SASSLYSGVP SRFSGSRSGT DFTLTISSLQ PEDFATYYC QQSSSSLITF GQGTKVEIKR TVAAPSVFIF PPSDSQLKSG TASVVCLLNN FYPREAKVQW KVDNALQSGN S QESVTEQD ...String:
SDIQMTQSPS SLSASVGDRV TITCRASQSV SSAVAWYQQK PGKAPKLLIY SASSLYSGVP SRFSGSRSGT DFTLTISSLQ PEDFATYYC QQSSSSLITF GQGTKVEIKR TVAAPSVFIF PPSDSQLKSG TASVVCLLNN FYPREAKVQW KVDNALQSGN S QESVTEQD SKDSTYSLSS TLTLSKADYE KHKVYACEVT HQGLSSPVTK SFNRGEC

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Macromolecule #6: 2-acetamido-2-deoxy-beta-D-glucopyranose

MacromoleculeName: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 6 / Number of copies: 1 / 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 stateparticle

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Sample preparation

BufferpH: 7.5
VitrificationCryogen name: ETHANE / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: TFS FALCON 4i (4k x 4k) / Average electron dose: 50.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.2 µm / Nominal defocus min: 0.6 µm / Nominal magnification: 165000
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: NONE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.14 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 101358
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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Atomic model buiding 1

Initial model
PDB IDChain

1y6k

chain_id: R, source_name: PDB, initial_model_type: experimental model

3lqm

chain_id: A, source_name: PDB, initial_model_type: experimental model

7pij

chain_id: H, source_name: PDB, initial_model_type: experimental model

7pij

chain_id: L, source_name: PDB, initial_model_type: experimental model
Output model

PDB-10ne:
Cryo-EM structure of human IL-10RA and IL-10RB in complex with tandem VHHs E07-A05

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