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TitleStructure-based decoupling of the pro- and anti-inflammatory functions of interleukin-10.
Journal, issue, pagesScience, Vol. 371, Issue 6535, Year 2021
Publish dateMar 19, 2021
AuthorsRobert A Saxton / Naotaka Tsutsumi / Leon L Su / Gita C Abhiraman / Kritika Mohan / Lukas T Henneberg / Nanda G Aduri / Cornelius Gati / K Christopher Garcia /
PubMed AbstractInterleukin-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.
External linksScience / PubMed:33737461 / PubMed Central
MethodsEM (single particle)
Resolution3.5 Å
Structure data

22098

6x93

EMDB-22098, PDB-6x93:
Interleukin-10 signaling complex with IL-10RA and IL-10RB
Method: EM (single particle) / Resolution: 3.5 Å

Source
  • homo sapiens (human)
KeywordsCYTOKINE / IL-10 / receptor / IL-10RA / IL-10RB / signaling

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