TERTIARY STRUCTURES OF ACTIVIN AND ACTIVIN RECEPTORS

这项拟议研究的长期目标是了解信号是如何 通过活细胞的细胞膜进行转换。神经肽/蛋白质 与它们的受体结合以发挥不同的生物功能， 为研究信号转导机制提供了良好的系统。 受体通常是跨膜蛋白，具有单一的 跨膜螺旋。一个共同的主题开始在这些人中出现 参与信号转导的受体。很明显， 配体与其受体的胞外区(S)的结合是 发信号的第一步。然而，对这一点的结构性理解 然后，绑定被传递到信令的下游组件 路径是非常需要的。一种思想流派认为，配体结合 受体诱导反应的寡聚(同源或异源) 感受器。这一概念形成了信令的基本基础 生长因子及生长因子样细胞因子的作用机制 作为肿瘤坏死因子。它通常被称为“受体聚集”，并且 已经提出了许多已知的细胞因子受体。晶体结构 人生长因子/受体复合体与肿瘤坏死 因子/受体复合体支持“受体聚集”的观点。 MHC II的晶体结构也表明了一种可能性 多肽/MHC II复合体诱导受体二聚化。在我们提议的 我们计划将重点放在激活素和激活素/受体复合体上。激活 以一种独特的方式与两种受体相互作用。与大多数不同 已知的跨膜受体是酪氨酸磷酸化，这一组 受体的一部分是丝氨酸/苏氨酸激酶活性。此外，只有类型 已知II型受体与激活素结合，尽管I型受体的结合 具有II型受体与配体的络合物的受体是 必填项。这两种受体都具有丝氨酸激酶活性。 胞质结构域，以及两者的活性是信号传递所必需的。 激活素的重组形式及激活素的配体结合域 受体现已大量上市。化学和生物物理 激活素及其受体的特征可能为研究 更好地理解互动的本质。晶体结构的研究 激活素及其与受体的络合物将通过X射线进行研究 结晶学方法。激活素和激活素的三维结构 激活素与其受体的复合体将提供一个很好的模型， 以原子分辨率定义绑定接口。构象 激活素结合反应的II型受体的变化可能触发 信号通路的进一步级联，提供了一个重要的线索 了解信令机制的结构基础 薄膜。定义神经肽结合特异性的原子模型 如激活素和促性腺激素释放激素也将促进 有效和长效的模拟多肽药物的设计 有助于调节各种与激素有关的疾病。

The long-term goal of the proposed study is to understand how signal is transduced across the membrane of a living cell. Neuropeptides/proteins bind to their receptors to exert different biological functions, providing a good system to study the mechanism of signal transduction. The receptors are often transmembrane proteins with a single transmembrane helix. A common theme begins to emerge among those receptors involved in signal transduction. It is apparent that the binding of a ligand to the extracellular domain of its receptor(s) is the first step of signaling. However, structural understanding of how this binding is then transduced to the downstream components of signaling pathway is much needed. One school of thought is that the ligand binding to a receptor induces an oligomerization (homo- or hetero-) of responsive receptors. This notion forms the underlying basis for the signaling mechanism of growth factor as well as growth factor-like cytokines such as tumor necrosis factor. It is commonly called "receptor clustering" and has been proposed for many known cytokine receptors. Crystal structures of human growth factor/receptor complex and tumor necrosis factor/receptor complex support the idea of "receptor clustering". Crystal structure of MHC II also suggests a possibility that the peptide/MHC II complex induces dimerization of receptors. In our proposed study, we plan to focus on activin and activin/receptor complex. Activin interacts with two types of receptors in a unique manner. Unlike most transmembrane receptors known to be tyrosine phosphorylating, this group of receptors is serine/threonine kinase active. In addition, only type II receptor is known to bind to activin although the binding of type I receptor with the complex of type II receptor with the ligand is required. Both types of receptors have serine kinase activity in their cytoplasmic domains, and the activity of both are required for signaling. Recombinant forms of activin and the ligand-binding domain of activin receptors are now available in quantity. Chemical and biophysical characterization of activin and its receptor may provide a clue to a better understanding of the nature of interaction. Crystal structures of activin and its complex with the receptor will be studied by X-ray crystallographic methods. The three-dimensional structures of activin and the complex of activin with its receptor would provide a good model, defining he binding interface at atomic resolution. Conformational changes of type II receptor responding to activin binding may trigger the further cascade of signaling pathway, providing an important clue is understanding the structural basis of signaling mechanism across the membrane. Atomic models defining the binding specificity of neuropeptides such as activin and gonadotropin-releasing hormone would also facilitate the design of effective and long-lasting peptidomimetic drugs that would be useful in modulating various hormone-related diseases.