+Open data
-Basic information
Entry | Database: EMDB / ID: EMD-22098 | |||||||||
---|---|---|---|---|---|---|---|---|---|---|
Title | Interleukin-10 signaling complex with IL-10RA and IL-10RB | |||||||||
Map data | Sharpened map of the hexameric Interleukin-10 signaling complex with IL-10RA and IL-10RB | |||||||||
Sample |
| |||||||||
Keywords | IL-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 activity / interleukin-10 receptor binding / regulation of response to wounding / negative regulation of cytokine 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 activity / interleukin-10 receptor binding / regulation of response to wounding / negative regulation of cytokine 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 / response to carbon monoxide / positive regulation of B cell apoptotic process / ubiquitin-dependent endocytosis / positive regulation of cellular respiration / chronic inflammatory response to antigenic stimulus / cytoplasmic sequestering of NF-kappaB / response to inactivity / negative regulation of membrane protein ectodomain proteolysis / positive regulation of plasma cell differentiation / regulation of isotype switching / intestinal epithelial structure maintenance / negative regulation of heterotypic cell-cell adhesion / branching involved in labyrinthine layer morphogenesis / negative regulation of cytokine production involved in immune response / type III interferon-mediated signaling pathway / negative regulation of interleukin-1 production / negative regulation of interleukin-8 production / negative regulation of MHC class II biosynthetic process / interleukin-10-mediated signaling pathway / negative regulation of nitric oxide biosynthetic process / negative regulation of interleukin-12 production / type 2 immune response / endothelial cell apoptotic process / negative regulation of oxidative stress-induced neuron intrinsic apoptotic signaling pathway / positive regulation of macrophage activation / positive regulation of MHC class II biosynthetic process / positive regulation of heterotypic cell-cell adhesion / leukocyte chemotaxis / positive regulation of signaling receptor activity / CD163 mediating an anti-inflammatory response / negative regulation of cytokine production / positive regulation of immunoglobulin production / Other interleukin signaling / cellular response to hepatocyte growth factor stimulus / Interleukin-20 family signaling / regulation of synapse organization / B cell proliferation / positive regulation of sprouting angiogenesis / negative regulation of B cell proliferation / defense response to protozoan / Interleukin-10 signaling / negative regulation of interleukin-6 production / negative regulation of vascular associated smooth muscle cell proliferation / hemopoiesis / negative regulation of type II interferon production / negative regulation of tumor necrosis factor production / negative regulation of mitotic cell cycle / positive regulation of cell cycle / coreceptor activity / Nuclear events stimulated by ALK signaling in cancer / response to glucocorticoid / negative regulation of T cell proliferation / positive regulation of vascular associated smooth muscle cell proliferation / positive regulation of endothelial cell proliferation / Gene and protein expression by JAK-STAT signaling after Interleukin-12 stimulation / B cell differentiation / negative regulation of autophagy / FCGR3A-mediated IL10 synthesis / response to activity / positive regulation of cytokine production / cytokine activity / cellular response to estradiol stimulus / liver regeneration / positive regulation of receptor signaling pathway via JAK-STAT / positive regulation of DNA-binding transcription factor activity / growth factor activity / response to insulin / response to molecule of bacterial origin / cytokine-mediated signaling pathway / cellular response to virus / negative regulation of inflammatory response / positive regulation of miRNA transcription / Signaling by ALK fusions and activated point mutants / signaling receptor activity / cellular response to lipopolysaccharide / regulation of gene expression / Interleukin-4 and Interleukin-13 signaling / defense response to virus / response to lipopolysaccharide / protein dimerization activity / defense response to bacterium / inflammatory response / immune response / response to xenobiotic stimulus / apical plasma membrane / negative regulation of cell population proliferation / negative regulation of apoptotic process / positive regulation of DNA-templated transcription / signal transduction Similarity search - Function | |||||||||
Biological species | Homo sapiens (human) | |||||||||
Method | single particle reconstruction / cryo EM / Resolution: 3.5 Å | |||||||||
Authors | Saxton RA / Tsutsumi N | |||||||||
Funding support | United States, 1 items
| |||||||||
Citation | Journal: 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 |
|
-Structure visualization
Movie |
Movie viewer |
---|---|
Structure viewer | EM map: SurfViewMolmilJmol/JSmol |
Supplemental images |
-Downloads & links
-EMDB archive
Map data | emd_22098.map.gz | 59.5 MB | EMDB map data format | |
---|---|---|---|---|
Header (meta data) | emd-22098-v30.xml emd-22098.xml | 19.4 KB 19.4 KB | Display Display | EMDB header |
Images | emd_22098.png | 269.4 KB | ||
Filedesc metadata | emd-22098.cif.gz | 6.2 KB | ||
Others | emd_22098_additional_1.map.gz | 32.1 MB | ||
Archive directory | http://ftp.pdbj.org/pub/emdb/structures/EMD-22098 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-22098 | HTTPS FTP |
-Validation report
Summary document | emd_22098_validation.pdf.gz | 507 KB | Display | EMDB validaton report |
---|---|---|---|---|
Full document | emd_22098_full_validation.pdf.gz | 506.6 KB | Display | |
Data in XML | emd_22098_validation.xml.gz | 6 KB | Display | |
Data in CIF | emd_22098_validation.cif.gz | 6.9 KB | Display | |
Arichive directory | https://ftp.pdbj.org/pub/emdb/validation_reports/EMD-22098 ftp://ftp.pdbj.org/pub/emdb/validation_reports/EMD-22098 | HTTPS FTP |
-Related structure data
Related structure data | 6x93MC M: atomic model generated by this map C: citing same article (ref.) |
---|---|
Similar structure data | |
EM raw data | EMPIAR-10557 (Title: Interleukin-10 signaling complex with IL-10RA and IL-10RB Data size: 5.4 TB Data #1: Unaligned dark-subtracted TIFF movies with a gain reference for the 3D reconstruction of EMD-22098. [micrographs - multiframe]) |
-Links
EMDB pages | EMDB (EBI/PDBe) / EMDataResource |
---|---|
Related items in Molecule of the Month |
-Map
File | Download / File: emd_22098.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Annotation | Sharpened map of the hexameric Interleukin-10 signaling complex with IL-10RA and IL-10RB | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Projections & slices | Image control
Images are generated by Spider. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Voxel size | X=Y=Z: 1.078 Å | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Density |
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Symmetry | Space group: 1 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Details | EMDB XML:
CCP4 map header:
|
-Supplemental data
-Additional map: Unsharpened map of the hexameric Interleukin-10 signaling complex...
File | emd_22098_additional_1.map | ||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Annotation | Unsharpened map of the hexameric Interleukin-10 signaling complex with IL-10RA and IL-10RB | ||||||||||||
Projections & Slices |
| ||||||||||||
Density Histograms |
-Sample components
-Entire : Interleukin-10 signaling complex with IL-10RA and IL-10RB
Entire | Name: Interleukin-10 signaling complex with IL-10RA and IL-10RB |
---|---|
Components |
|
-Supramolecule #1: Interleukin-10 signaling complex with IL-10RA and IL-10RB
Supramolecule | Name: Interleukin-10 signaling complex with IL-10RA and IL-10RB type: complex / ID: 1 / Parent: 0 / Macromolecule list: all |
---|---|
Molecular weight | Theoretical: 130 KDa |
-Supramolecule #2: Interleukin-10, IL-10RA
Supramolecule | Name: Interleukin-10, IL-10RA / type: complex / ID: 2 / Parent: 1 / Macromolecule list: #1-#2 |
---|---|
Source (natural) | Organism: Homo sapiens (human) |
-Supramolecule #3: IL-10RB
Supramolecule | Name: IL-10RB / type: complex / ID: 3 / Parent: 1 / Macromolecule list: #3 |
---|---|
Source (natural) | Organism: Homo sapiens (human) |
-Macromolecule #1: Interleukin-10
Macromolecule | Name: Interleukin-10 / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO |
---|---|
Source (natural) | Organism: Homo sapiens (human) |
Molecular weight | Theoretical: 18.778543 KDa |
Recombinant expression | Organism: Homo sapiens (human) |
Sequence | String: SPGQGTQSEN SCTHFPGYLP NMLRDLRDAF SRVKTFFQMK DQLDNLLLKE SLLEDFKGYL GCQALSEMIQ FYLEEVMPQA ENQDPDIKA HVQSLGENLK DLRLWLRRCH RFLPCENKSK AVEQVKNAFN KLQEKGIYKA MSEFDIFINY IEAYMTMKIR N UniProtKB: Interleukin-10 |
-Macromolecule #2: Interleukin-10 receptor subunit alpha
Macromolecule | Name: Interleukin-10 receptor subunit alpha / type: protein_or_peptide / ID: 2 / Number of copies: 2 / Enantiomer: LEVO |
---|---|
Source (natural) | Organism: Homo sapiens (human) |
Molecular weight | Theoretical: 24.422391 KDa |
Recombinant expression | Organism: Homo sapiens (human) |
Sequence | String: 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 |
-Macromolecule #3: Interleukin-10 receptor subunit beta
Macromolecule | Name: Interleukin-10 receptor subunit beta / type: protein_or_peptide / ID: 3 / Number of copies: 2 / Enantiomer: LEVO |
---|---|
Source (natural) | Organism: Homo sapiens (human) |
Molecular weight | Theoretical: 23.569334 KDa |
Recombinant expression | Organism: Trichoplusia ni (cabbage looper) |
Sequence | String: 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 |
-Experimental details
-Structure determination
Method | cryo EM |
---|---|
Processing | single particle reconstruction |
Aggregation state | particle |
-Sample preparation
Concentration | 10 mg/mL | ||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Buffer | pH: 7.2 Component:
| ||||||||||||
Grid | Model: Quantifoil R1.2/1.3 / Material: GOLD / Mesh: 300 / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Time: 40 sec. | ||||||||||||
Vitrification | Cryogen name: ETHANE / Chamber humidity: 95 % / Chamber temperature: 293 K / Instrument: LEICA EM GP / Details: 5s blotting. |
-Electron microscopy
Microscope | FEI TITAN KRIOS |
---|---|
Specialist optics | Energy filter - Name: GIF Bioquantum / Energy filter - Slit width: 20 eV |
Image recording | Film or detector model: GATAN K3 (6k x 4k) / Number grids imaged: 1 / Number real images: 9413 / Average electron dose: 50.0 e/Å2 |
Electron beam | Acceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN |
Electron optics | C2 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 stage | Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN |
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |