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

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Basic information

Entry
Database: PDB / ID: 6x93
TitleInterleukin-10 signaling complex with IL-10RA and IL-10RB
Components
  • Interleukin-10
  • Interleukin-10 receptor subunit alpha
  • Interleukin-10 receptor subunit beta
KeywordsCYTOKINE / IL-10 / 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 / negative regulation of interleukin-18 production / interleukin-28 receptor complex / 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 / negative regulation of interleukin-18 production / interleukin-28 receptor complex / 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 cellular respiration / chronic inflammatory response to antigenic stimulus / response to inactivity / negative regulation of membrane protein ectodomain proteolysis / positive regulation of plasma cell differentiation / ubiquitin-dependent endocytosis / positive regulation of B cell apoptotic process / regulation of isotype switching / negative regulation of heterotypic cell-cell adhesion / negative regulation of cytokine production involved in immune response / type III interferon-mediated signaling pathway / negative regulation of MHC class II biosynthetic process / negative regulation of interleukin-1 production / intestinal epithelial structure maintenance / interleukin-10-mediated signaling pathway / branching involved in labyrinthine layer morphogenesis / negative regulation of interleukin-8 production / negative regulation of nitric oxide biosynthetic process / negative regulation of interleukin-12 production / response to carbon monoxide / endothelial cell apoptotic process / positive regulation of MHC class II biosynthetic process / positive regulation of macrophage activation / positive regulation of heterotypic cell-cell adhesion / negative regulation of oxidative stress-induced neuron intrinsic apoptotic signaling pathway / leukocyte chemotaxis / negative regulation of mitotic cell cycle / type 2 immune response / CD163 mediating an anti-inflammatory response / Other interleukin signaling / negative regulation of cytokine production / positive regulation of immunoglobulin production / Interleukin-20 family signaling / cellular response to hepatocyte growth factor stimulus / negative regulation of B cell proliferation / defense response to protozoan / regulation of synapse organization / positive regulation of sprouting angiogenesis / Interleukin-10 signaling / negative regulation of interleukin-6 production / negative regulation of type II interferon production / B cell proliferation / hemopoiesis / negative regulation of vascular associated smooth muscle cell proliferation / negative regulation of tumor necrosis factor production / positive regulation of DNA-binding transcription factor activity / Nuclear events stimulated by ALK signaling in cancer / coreceptor activity / positive regulation of vascular associated smooth muscle cell proliferation / negative regulation of T cell proliferation / positive regulation of cell cycle / positive regulation of endothelial cell proliferation / liver regeneration / Gene and protein expression by JAK-STAT signaling after Interleukin-12 stimulation / negative regulation of autophagy / FCGR3A-mediated IL10 synthesis / response to glucocorticoid / positive regulation of cytokine production / B cell differentiation / cytokine activity / response to activity / positive regulation of receptor signaling pathway via JAK-STAT / growth factor activity / cellular response to estradiol stimulus / response to molecule of bacterial origin / response to insulin / cellular response to virus / positive regulation of miRNA transcription / negative regulation of inflammatory response / cytokine-mediated signaling pathway / 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 / response to lipopolysaccharide / defense response to virus / protein dimerization activity / defense response to bacterium / immune response / cilium / apical plasma membrane / response to xenobiotic stimulus / inflammatory response / 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)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.5 Å
AuthorsSaxton, R.A. / Tsutsumi, N. / Gati, C. / Garcia, K.C.
Funding support United States, 1items
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, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 17, 2021Provider: repository / Type: Initial release
Revision 1.1Mar 31, 2021Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.pdbx_database_id_PubMed ..._citation.journal_volume / _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.identifier_ORCID
Revision 1.2Oct 16, 2024Group: Data collection / Database references ...Data collection / Database references / Refinement description / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / em_3d_fitting_list / em_admin / pdbx_entry_details / pdbx_initial_refinement_model / pdbx_modification_feature
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _em_3d_fitting_list.accession_code / _em_3d_fitting_list.initial_refinement_model_id / _em_3d_fitting_list.source_name / _em_3d_fitting_list.type / _em_admin.last_update

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Structure visualization

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Structure viewerMolecule:
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Assembly

Deposited unit
A: Interleukin-10
B: Interleukin-10 receptor subunit alpha
C: Interleukin-10 receptor subunit beta
D: Interleukin-10
E: Interleukin-10 receptor subunit alpha
F: Interleukin-10 receptor subunit beta


Theoretical massNumber of molelcules
Total (without water)133,5416
Polymers133,5416
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein Interleukin-10 / IL-10 / Cytokine synthesis inhibitory factor / CSIF


Mass: 18778.543 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: IL10 / Production host: Homo sapiens (human) / References: UniProt: P22301
#2: Protein Interleukin-10 receptor subunit alpha / IL-10RA / CDw210a / Interleukin-10 receptor subunit 1 / IL-10R1


Mass: 24422.391 Da / Num. of mol.: 2
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
#3: Protein Interleukin-10 receptor subunit beta / IL-10RB / Cytokine receptor class-II member 4 / Cytokine receptor family 2 member 4 / CRF2-4 / ...IL-10RB / Cytokine receptor class-II member 4 / Cytokine receptor family 2 member 4 / CRF2-4 / Interleukin-10 receptor subunit 2 / IL-10R2


Mass: 23569.334 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: IL10RB, CRFB4, D21S58, D21S66 / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: Q08334
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

Component
IDNameTypeEntity IDParent-IDSource
1Interleukin-10 signaling complex with IL-10RA and IL-10RBCOMPLEXall0MULTIPLE SOURCES
2Interleukin-10, IL-10RACOMPLEX#1-#21RECOMBINANT
3IL-10RBCOMPLEX#31RECOMBINANT
Molecular weightValue: 0.13 MDa / Experimental value: NO
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
12Homo sapiens (human)9606
23Homo sapiens (human)9606
Source (recombinant)
IDEntity assembly-IDOrganismNcbi tax-ID
12Homo sapiens (human)9606
23Trichoplusia ni (cabbage looper)7111
Buffer solutionpH: 7.2
Buffer component
IDConc.NameBuffer-ID
110 mMHEPES1
2150 mMSodium chloride1
30.001 % (w/v)GDN1
40.0001 % (w/v)CHS1
50.05 % (w/v)Digitonin1
SpecimenConc.: 10 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: GOLD / Grid mesh size: 300 divisions/in. / Grid type: Quantifoil R1.2/1.3
VitrificationInstrument: LEICA EM GP / Cryogen name: ETHANE / Humidity: 95 % / Chamber temperature: 293 K / Details: 5s blotting

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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 magnification: 81000 X / Nominal defocus max: -2000 nm / Nominal defocus min: -800 nm / Cs: 2.7 mm / C2 aperture diameter: 100 µm / Alignment procedure: COMA FREE
Specimen holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingElectron dose: 50 e/Å2 / Film or detector model: GATAN K3 (6k x 4k) / Num. of grids imaged: 1 / Num. of real images: 9413
EM imaging opticsEnergyfilter name: GIF Bioquantum / Energyfilter slit width: 20 eV

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Processing

Software
NameVersionClassification
phenix.real_space_refine1.17.1_3660refinement
PHENIX1.17.1_3660refinement
EM software
IDNameCategory
1cryoSPARCparticle selection
2SerialEMimage acquisition
4cryoSPARCCTF correction
7PHENIXmodel fitting
9cryoSPARCinitial Euler assignment
10cryoSPARCfinal Euler assignment
11cryoSPARCclassification
12cryoSPARC3D reconstruction
19PHENIXmodel refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNum. of particles selected: 6701298
SymmetryPoint symmetry: C1 (asymmetric)
3D reconstructionResolution: 3.5 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 86725 / Symmetry type: POINT
Atomic model buildingProtocol: FLEXIBLE FIT / Space: REAL
Atomic model building
IDPDB-ID 3D fitting-IDAccession codeInitial refinement model-IDSource nameType
11Y6K

1y6k

11Y6K1PDBexperimental model
23LQM

3lqm

13LQM2PDBexperimental model
RefinementCross valid method: NONE
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
Displacement parametersBiso mean: 76.12 Å2
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00746951
ELECTRON MICROSCOPYf_angle_d1.12879517
ELECTRON MICROSCOPYf_chiral_restr0.05761140
ELECTRON MICROSCOPYf_plane_restr0.00691273
ELECTRON MICROSCOPYf_dihedral_angle_d19.61742116

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