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- EMDB-22098: Interleukin-10 signaling complex with IL-10RA and IL-10RB -

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Basic information

Entry
Database: EMDB / ID: EMD-22098
TitleInterleukin-10 signaling complex with IL-10RA and IL-10RB
Map dataSharpened map of the hexameric Interleukin-10 signaling complex with IL-10RA and IL-10RB
Sample
  • Complex: Interleukin-10 signaling complex with IL-10RA and IL-10RB
    • Complex: Interleukin-10, IL-10RA
      • Protein or peptide: Interleukin-10
      • Protein or peptide: Interleukin-10 receptor subunit alpha
    • Complex: IL-10RB
      • Protein or peptide: Interleukin-10 receptor subunit beta
KeywordsIL-10 / cytokine / receptor / IL-10RA / IL-10RB / signaling
Function / homology
Function and homology information


interleukin-10 binding / negative regulation of chronic inflammatory response to antigenic stimulus / interleukin-10 receptor binding / regulation of response to wounding / negative regulation of cytokine activity / interleukin-10 receptor activity / interleukin-28 receptor complex / negative regulation of interleukin-18 production / negative regulation of myeloid dendritic cell activation / negative regulation of interferon-alpha production ...interleukin-10 binding / negative regulation of chronic inflammatory response to antigenic stimulus / interleukin-10 receptor binding / regulation of response to wounding / negative regulation of cytokine activity / interleukin-10 receptor activity / interleukin-28 receptor complex / negative regulation of interleukin-18 production / negative regulation of myeloid dendritic cell activation / negative regulation of interferon-alpha production / negative regulation of chemokine (C-C motif) ligand 5 production / positive regulation of B cell apoptotic process / ubiquitin-dependent endocytosis / : / chronic inflammatory response to antigenic stimulus / response to inactivity / positive regulation of cellular respiration / type III interferon-mediated signaling pathway / negative regulation of membrane protein ectodomain proteolysis / positive regulation of plasma cell differentiation / response to carbon monoxide / regulation of isotype switching / negative regulation of heterotypic cell-cell adhesion / interleukin-10-mediated signaling pathway / negative regulation of cytokine production involved in immune response / negative regulation of interleukin-1 production / negative regulation of MHC class II biosynthetic process / branching involved in labyrinthine layer morphogenesis / intestinal epithelial structure maintenance / negative regulation of nitric oxide biosynthetic process / negative regulation of interleukin-8 production / negative regulation of interleukin-12 production / endothelial cell apoptotic process / positive regulation of MHC class II biosynthetic process / positive regulation of macrophage activation / negative regulation of oxidative stress-induced neuron intrinsic apoptotic signaling pathway / positive regulation of heterotypic cell-cell adhesion / leukocyte chemotaxis / type 2 immune response / Other interleukin signaling / CD163 mediating an anti-inflammatory response / negative regulation of cytokine production / Interleukin-20 family signaling / positive regulation of immunoglobulin production / cellular response to hepatocyte growth factor stimulus / negative regulation of B cell proliferation / regulation of synapse organization / defense response to protozoan / positive regulation of sprouting angiogenesis / Interleukin-10 signaling / negative regulation of vascular associated smooth muscle cell proliferation / hemopoiesis / negative regulation of interleukin-6 production / negative regulation of type II interferon production / B cell proliferation / negative regulation of mitotic cell cycle / negative regulation of tumor necrosis factor production / response to glucocorticoid / coreceptor activity / Nuclear events stimulated by ALK signaling in cancer / positive regulation of vascular associated smooth muscle cell proliferation / positive regulation of cell cycle / negative regulation of T cell proliferation / positive regulation of endothelial cell proliferation / Gene and protein expression by JAK-STAT signaling after Interleukin-12 stimulation / negative regulation of autophagy / B cell differentiation / FCGR3A-mediated IL10 synthesis / positive regulation of DNA-binding transcription factor activity / liver regeneration / cytokine activity / positive regulation of cytokine production / response to activity / positive regulation of receptor signaling pathway via JAK-STAT / response to insulin / growth factor activity / cellular response to estradiol stimulus / response to molecule of bacterial origin / cytokine-mediated signaling pathway / cellular response to virus / positive regulation of miRNA transcription / negative regulation of inflammatory response / Signaling by ALK fusions and activated point mutants / signaling receptor activity / regulation of gene expression / cellular response to lipopolysaccharide / Interleukin-4 and Interleukin-13 signaling / defense response to virus / response to lipopolysaccharide / protein dimerization activity / defense response to bacterium / immune response / apical plasma membrane / inflammatory response / response to xenobiotic stimulus / negative regulation of cell population proliferation / negative regulation of apoptotic process / positive regulation of DNA-templated transcription / signal transduction / positive regulation of transcription by RNA polymerase II
Similarity search - Function
Interleukin-10 / Interleukin-10 family / Interleukin 10 / Interleukin-10/19/20/22/24/26 family / Interleukin-10, conserved site / Interleukin-10 family signature. / Interferon/interleukin receptor domain / Interferon-alpha/beta receptor, fibronectin type III / : / Tissue factor ...Interleukin-10 / Interleukin-10 family / Interleukin 10 / Interleukin-10/19/20/22/24/26 family / Interleukin-10, conserved site / Interleukin-10 family signature. / Interferon/interleukin receptor domain / Interferon-alpha/beta receptor, fibronectin type III / : / Tissue factor / Four-helical cytokine-like, core / Fibronectin type-III domain profile. / Fibronectin type III / Fibronectin type III superfamily / Immunoglobulin-like fold
Similarity search - Domain/homology
Interleukin-10 / Interleukin-10 receptor subunit beta / Interleukin-10 receptor subunit alpha
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.5 Å
AuthorsSaxton RA / Tsutsumi N
Funding support United States, 1 items
OrganizationGrant numberCountry
Department of Energy (DOE, United States)DE-AC02-76SF00515 United States
CitationJournal: Science / Year: 2021
Title: Structure-based decoupling of the pro- and anti-inflammatory functions of interleukin-10.
Authors: Robert A Saxton / Naotaka Tsutsumi / Leon L Su / Gita C Abhiraman / Kritika Mohan / Lukas T Henneberg / Nanda G Aduri / Cornelius Gati / K Christopher Garcia /
Abstract: Interleukin-10 (IL-10) is an immunoregulatory cytokine with both anti-inflammatory and immunostimulatory properties and is frequently dysregulated in disease. We used a structure-based approach to ...Interleukin-10 (IL-10) is an immunoregulatory cytokine with both anti-inflammatory and immunostimulatory properties and is frequently dysregulated in disease. We used a structure-based approach to deconvolute IL-10 pleiotropy by determining the structure of the IL-10 receptor (IL-10R) complex by cryo-electron microscopy at a resolution of 3.5 angstroms. The hexameric structure shows how IL-10 and IL-10Rα form a composite surface to engage the shared signaling receptor IL-10Rβ, enabling the design of partial agonists. IL-10 variants with a range of IL-10Rβ binding strengths uncovered substantial differences in response thresholds across immune cell populations, providing a means of manipulating IL-10 cell type selectivity. Some variants displayed myeloid-biased activity by suppressing macrophage activation without stimulating inflammatory CD8 T cells, thereby uncoupling the major opposing functions of IL-10. These results provide a mechanistic blueprint for tuning the pleiotropic actions of IL-10.
History
DepositionJun 2, 2020-
Header (metadata) releaseMar 17, 2021-
Map releaseMar 17, 2021-
UpdateOct 16, 2024-
Current statusOct 16, 2024Processing site: RCSB / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.4
  • Imaged by UCSF Chimera
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  • Surface view colored by cylindrical radius
  • Surface level: 0.4
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-6x93
  • Surface level: 0.4
  • Imaged by UCSF Chimera
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  • Simplified surface model + fitted atomic model
  • Atomic modelsPDB-6x93
  • Imaged by Jmol
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_22098.png

Downloads & links

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Map

FileDownload / File: emd_22098.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationSharpened map of the hexameric Interleukin-10 signaling complex with IL-10RA and IL-10RB
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.08 Å/pix.
x 256 pix.
= 275.968 Å		1.08 Å/pix.
x 256 pix.
= 275.968 Å		1.08 Å/pix.
x 256 pix.
= 275.968 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.078 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.4 / Movie #1: 0.4
Minimum - Maximum-1.4334321 - 2.4508932
Average (Standard dev.)-0.00008663789 (±0.047957122)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 275.968 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.0781.0781.078
M x/y/z256256256
origin x/y/z0.0000.0000.000
length x/y/z275.968275.968275.968
α/β/γ90.00090.00090.000
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS256256256
D min/max/mean-1.4332.451-0.000

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Supplemental data

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Additional map: Unsharpened map of the hexameric Interleukin-10 signaling complex...

Fileemd_22098_additional_1.map
AnnotationUnsharpened map of the hexameric Interleukin-10 signaling complex with IL-10RA and IL-10RB
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Interleukin-10 signaling complex with IL-10RA and IL-10RB

EntireName: Interleukin-10 signaling complex with IL-10RA and IL-10RB
Components
  • Complex: Interleukin-10 signaling complex with IL-10RA and IL-10RB
    • Complex: Interleukin-10, IL-10RA
      • Protein or peptide: Interleukin-10
      • Protein or peptide: Interleukin-10 receptor subunit alpha
    • Complex: IL-10RB
      • Protein or peptide: Interleukin-10 receptor subunit beta

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Supramolecule #1: Interleukin-10 signaling complex with IL-10RA and IL-10RB

SupramoleculeName: Interleukin-10 signaling complex with IL-10RA and IL-10RB
type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Molecular weightTheoretical: 130 KDa

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Supramolecule #2: Interleukin-10, IL-10RA

SupramoleculeName: Interleukin-10, IL-10RA / type: complex / ID: 2 / Parent: 1 / Macromolecule list: #1-#2
Source (natural)Organism: Homo sapiens (human)

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Supramolecule #3: IL-10RB

SupramoleculeName: IL-10RB / type: complex / ID: 3 / Parent: 1 / Macromolecule list: #3
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Interleukin-10

MacromoleculeName: Interleukin-10 / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 18.778543 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString:
SPGQGTQSEN SCTHFPGYLP NMLRDLRDAF SRVKTFFQMK DQLDNLLLKE SLLEDFKGYL GCQALSEMIQ FYLEEVMPQA ENQDPDIKA HVQSLGENLK DLRLWLRRCH RFLPCENKSK AVEQVKNAFN KLQEKGIYKA MSEFDIFINY IEAYMTMKIR N

UniProtKB: Interleukin-10

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Macromolecule #2: Interleukin-10 receptor subunit alpha

MacromoleculeName: Interleukin-10 receptor subunit alpha / type: protein_or_peptide / ID: 2 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 24.422391 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 YFTVTN

UniProtKB: Interleukin-10 receptor subunit alpha

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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: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 23.569334 KDa
Recombinant expressionOrganism: Trichoplusia ni (cabbage looper)
SequenceString: MVPPPENVRM NSVNFKNILQ WESPAFAKGQ LTFTAQYLSY RIFQDKCMQT TLTECDFSSL SKYGDHTLRV RAEFADEHSD WVQITFCPV DDTIIGPPGM QVEVLADSLH MRFLAPKIEN EYETWTMKNV YNSWTYNVQY WKNGTDEKFQ ITPQYDFEVL R NLEPWTTY ...String:
MVPPPENVRM NSVNFKNILQ WESPAFAKGQ LTFTAQYLSY RIFQDKCMQT TLTECDFSSL SKYGDHTLRV RAEFADEHSD WVQITFCPV DDTIIGPPGM QVEVLADSLH MRFLAPKIEN EYETWTMKNV YNSWTYNVQY WKNGTDEKFQ ITPQYDFEVL R NLEPWTTY CVQVRGFLPD RNKAGEWSEP VCEQTTHDET VPS

UniProtKB: Interleukin-10 receptor subunit beta

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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

Concentration10 mg/mL
BufferpH: 7.2
Component:
ConcentrationName
10.0 mMHEPES
150.0 mMSodium chloride
0.001 % (w/v)GDN
0.0001 % (w/v)CHS
0.05 % (w/v)Digitonin
GridModel: Quantifoil R1.2/1.3 / Material: GOLD / Mesh: 300 / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Time: 40 sec.
VitrificationCryogen name: ETHANE / Chamber humidity: 95 % / Chamber temperature: 293 K / Instrument: LEICA EM GP / Details: 5s blotting.

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Specialist opticsEnergy filter - Name: GIF Bioquantum / Energy filter - Slit width: 20 eV
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Number grids imaged: 1 / Number real images: 9413 / Average electron dose: 50.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsC2 aperture diameter: 100.0 µm / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: -2.0 µm / Nominal defocus min: -0.8 µm / Nominal magnification: 81000
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 6701298
Startup modelType of model: OTHER / Details: Initial model generation in cryoSPARC.
Final reconstructionApplied symmetry - Point group: C1 (asymmetric) / Resolution.type: BY AUTHOR / Resolution: 3.5 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 86725
Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC

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Atomic model buiding 1

Initial model
PDB IDChain

1y6k

source_name: PDB, initial_model_type: experimental model

3lqm

source_name: PDB, initial_model_type: experimental model
RefinementSpace: REAL / Protocol: FLEXIBLE FIT
Output model

PDB-6x93:
Interleukin-10 signaling complex with IL-10RA and IL-10RB

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