Department of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, Victoria, 3010, Australia.
Center for Structural Biology, Center for Cancer Research, National Cancer Institute, Frederick, Maryland, 21702, USA.
Nat Commun. 2023 Nov 20;14(1):7543. doi: 10.1038/s41467-023-42754-w.
Interleukin (IL-)11, an IL-6 family cytokine, has pivotal roles in autoimmune diseases, fibrotic complications, and solid cancers. Despite intense therapeutic targeting efforts, structural understanding of IL-11 signalling and mechanistic insights into current inhibitors are lacking. Here we present cryo-EM and crystal structures of the human IL-11 signalling complex, including the complex containing the complete extracellular domains of the shared IL-6 family β-receptor, gp130. We show that complex formation requires conformational reorganisation of IL-11 and that the membrane-proximal domains of gp130 are dynamic. We demonstrate that the cytokine mutant, IL-11 Mutein, competitively inhibits signalling in human cell lines. Structural shifts in IL-11 Mutein underlie inhibition by altering cytokine binding interactions at all three receptor-engaging sites and abrogating the final gp130 binding step. Our results reveal the structural basis of IL-11 signalling, define the molecular mechanisms of an inhibitor, and advance understanding of gp130-containing receptor complexes, with potential applications in therapeutic development.
白细胞介素 (IL-)11 是一种白细胞介素 6 家族细胞因子，在自身免疫性疾病、纤维化并发症和实体瘤中发挥着关键作用。尽管进行了大量的治疗靶向研究，但人们对 IL-11 信号传导的结构理解以及对现有抑制剂的机制见解仍有所欠缺。在这里，我们展示了人类 IL-11 信号复合物的冷冻电镜和晶体结构，包括包含共享白细胞介素 6 家族β受体 gp130 的完整细胞外结构域的复合物。我们表明，复合物的形成需要 IL-11 的构象重排，并且 gp130 的膜近端结构域是动态的。我们证明，细胞因子突变体 IL-11 Mutein 在人细胞系中竞争性抑制信号转导。IL-11 Mutein 的结构变化通过改变所有三个受体结合位点的细胞因子结合相互作用以及阻断 gp130 的最终结合步骤来抑制信号转导。我们的研究结果揭示了 IL-11 信号传导的结构基础，定义了抑制剂的分子机制，并加深了对包含 gp130 的受体复合物的理解，这在治疗开发方面具有潜在的应用。
