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-Structure paper
タイトル | Structure-based decoupling of the pro- and anti-inflammatory functions of interleukin-10. |
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ジャーナル・号・ページ | Science, Vol. 371, Issue 6535, Year 2021 |
掲載日 | 2021年3月19日 |
著者 | Robert A Saxton / Naotaka Tsutsumi / Leon L Su / Gita C Abhiraman / Kritika Mohan / Lukas T Henneberg / Nanda G Aduri / Cornelius Gati / K Christopher Garcia / |
PubMed 要旨 | 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. |
リンク | Science / PubMed:33737461 / PubMed Central |
手法 | EM (単粒子) |
解像度 | 3.5 Å |
構造データ | EMDB-22098, PDB-6x93: |
由来 |
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キーワード | CYTOKINE / IL-10 / receptor / IL-10RA / IL-10RB / signaling |