STRUCTURE STUDIES ON PROTEINS THAT MODULATE IL-10 ACTION

描述：(摘自申请者的摘要)本研究的总体目标 是确定蛋白质-蛋白质相互作用的结构基础 利用晶体结构调控白介素10的生物学活性 IL-10与其细胞表面受体结合的结构及几种Fab 用X射线衍射法测定中和抗体的碎片。这些 数据将用于设计增强或阻止IL-10/IL-10的IL-10突变体 受体的相互作用以及改变几何构型和/或 IL-10受体-配体复合体的化学计量。形成一种复合体 由IL-10、高亲和力受体(IL-10Rpha)和信号组成 转导受体(IL-10Rβ)是产生IL-10所必需的 抑制TH1依赖的细胞免疫的生物活性 回应。由于这些活性，IL-10是一种非常有希望的蛋白质 治疗慢性炎症性疾病。IL-10是 目前正处于克罗恩病的第三阶段临床试验和第二阶段试验 风湿性关节炎影响了4000万人，并使国家付出了代价 每年有超过650亿美元的工作残疾。除了它的 免疫抑制作用，IL-10被认为是一种自分泌生长因子 在几种B细胞恶性肿瘤的发病机制中负有责任。因此， IL-10拮抗剂具有潜在的治疗应用前景。

Description: (From the applicant's abstract) The overall goal of this research is to identify the structural basis for protein-protein interactions that modulate interleukin 10 (IL-10) biological activities by elucidating crystal structures of IL-10 complexed with its cell surface receptors, and several Fab fragments of neutralizing antibodies using X-ray diffraction techniques. These data will be used to design IL-10 mutants that enhance or prevent IL-10/IL-10 receptor interactions as well as mutants that change the geometry and/or the stoichiometry of the IL-10 receptor-ligand complex. Formation of a complex consisting of IL-10, a high affinity receptor (IL-10Ralpha), and a signal transducing receptor (IL-10Rbeta) is required for the generation of IL-10 biological activities that suppress TH1-dependent, cell-mediated immune responses. As a result of these activities, IL-10 is a very promising protein therapeutic for the treatment of chronic inflammatory diseases. IL-10 is currently in phase III clinical trials for Crohn's disease and phase II trials for rheumatoid arthritis that affects 40 million people and costs the country over 65 billion dollars annually in work disability. In addition to its immunosuppressive role, IL-10 has been implicated as an autocrine growth factor responsible in the pathogenesis of several B-cell malignancies. Thus, antagonists of IL-10 have potential therapeutic applications.