Ternary ligand-receptor complex formation by IL-5 and its inhibition by small peptides

IL-5三元配体-受体复合物的形成及其小肽的抑制

• 批准号: 234282273
• 负责人: Professor Dr. Thomas Müller
• 金额: --
• 依托单位: Lehrstuhl für Botanik I: Molekulare Pflanzenphysiologie und Biophysik
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2013
• 资助国家: 德国
• 起止时间: 2012-12-31 至 2016-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/234282273?language=en
• 关键词: Ternary; ligand; receptor; complex; formation

Interleukin-5 (IL-5) is a classical TH2 cytokine playing a pivotal role in almost any aspect of eosin-ophil life, starting with differentiation from progenitor cells, migration, proliferation to their activation. Thus deregulation of IL-5 signaling manifests in development and progression of hypereosinophilic diseases characterized by massive proliferation and infiltration of eosinophils into different tissues and organs, where eosinophil activation can subsequently lead to severe damage of the organ. Thus IL-5 has become a major target for therapeutic intervention in diseases such as allergic asthma, eosinophilic esophagitis, hypereosinophilic diseases or the Churg-Strauss syndrome. Anti-IL-5 neutralizing antibodies have shown relieve from disease symptoms in hypereosinophilic syn-dromes affecting the gastrointestinal tract. Short cyclic peptides blocking IL-5 receptor activation have been developed potentially providing a more cost-effective strategy for an anti-IL-5 therapy. Thus an in-depth understanding of the molecular mechanism underlying IL-5 signaling is a prereq-uisite for the development or improvement of IL-5 inhibitors possibly counteracting these diseases. Recently we could make a huge step towards understanding the molecular mechanism of this is-sue by solving the crystal structure of the binary complex of IL-5 bound to its receptor IL-5Ralpha. The structure shows a new unusual architecture for the IL 5Ralpha:IL-5 interaction with the wrench IL-5Ralpha encompassing the nut IL-5. Mutagenesis in concert with in vitro interaction analysis revealed the functional epitope for the IL-5Ralpha:IL-5 interaction showing that the first of the three Fibronectin type III domains of the receptor comprising the hotspot of the receptor-ligand interaction. However, signaling of IL-5 requires formation of a ternary complex of IL-5 bound to IL-5Ralpha and the subunit common-beta, the latter of which is shared with IL-3 and GM-CSF. Recent analyses of the ternary ligand-receptor complex of GM-CSF however challenged the paradigm of the ligand just dimerizing two receptor subunits to initiate signal transduction. Rather than a receptor heterodimer a higher-order complex is formed raising the question how ligand-specific signals are provided. To gain insight into the IL-5 receptor activation and potential differences to that of GM-CSF we propose structure analysis of the full, signaling-competent ternary IL-5:IL-5Ralpha:common-beta complex. In parallel, we plan to solve structures of peptide-based IL-5 inhibitors bound to IL-5Ralpha providing an insight into their inhibition mechanism, which will then allow to design new peptidomimetics or refine these peptides. This project attempts to get a comprehensive view on the mechanisms of IL-5 complex formation and signal activation with the goal to facilitate the generation of novel IL-5 inhibitors that might be based on small compounds, peptides or mutant proteins.

白介素5（IL-5）是一种经典的Th2细胞因子，在曙红 - 磷脂寿命的几乎任何方面都起着关键作用，从从祖细胞分化，迁移，增殖到其激活开始。因此，对IL-5信号传导的放松调节表现出以大规模增殖和嗜酸性粒细胞浸润到不同组织和器官的发育和发展中的发育和进展，其中嗜酸性粒细胞激活可能随后会导致器官的严重损害。因此，IL-5已成为治疗干预疾病的主要靶标，例如过敏性哮喘，嗜酸性食管炎，嗜酸性疾病或Churg-Strauss综合征。抗IL-5中和抗体已经缓解了影响胃肠道的嗜性粒细胞同步症中的疾病症状。已经开发出了短循环肽阻断IL-5受体激活，可能为抗IL-5治疗提供了更具成本效益的策略。因此，对IL-5信号传导的分子机制的深入了解是开发或改善IL-5抑制剂可能抵消这些疾病的预替石。最近，我们可以通过求解与其受体IL-5ralpha结合的IL-5的二元复合物的晶体结构来迈出迈向理解该分子机制的巨大步骤。该结构显示了IL 5ralpha：IL-5与扳手IL-5ralpha的相互作用的新的异常结构，该结构包含Nut IL-5。与体外相互作用分析一致的诱变揭示了IL-5ralpha：IL-5相互作用的功能表位，表明受体 - 配体相互作用的热点的受体的三个纤连蛋白III型III型结构域中的第一个。但是，IL-5的信号需要形成与IL-5ralpha和亚基commen-Beta结合的IL-5的三元复合物，后者与IL-3和GM-CSF共享。然而，GM-CSF的三元配体 - 受体复合物的最新分析挑战了配体的范式，只是将两个受体亚基降低以启动信号转导。而不是受体异二聚体形成高阶复合物，从而提出了如何提供配体特异性信号的问题。为了深入了解IL-5受体激活和与GM-CSF的受体的潜在差异，我们提出了对完整的，具有信号能力的三元IL-5：IL-5ralpha的结构分析：IL-5ralpha：commun-beta complect。同时，我们计划解决与IL-5ralpha结合的基于肽的IL-5抑制剂的结构，从而提供了对其抑制机制的见解，然后将允许设计新的肽仪或完善这些肽。该项目试图对IL-5复合物形成和信号激活的机制进行全面的看法，目的是促进可能基于小化合物，肽或突变蛋白的新型IL-5抑制剂的产生。