NEW SIGNALING PATHWAY PROBES BASED ON NATURAL TOXINS

基于天然毒素的新信号通路探针

• 批准号: 6386897
• 负责人: A RICHARD CHAMBERLIN
• 金额: $ 21.81万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-08-01 至 2002-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6386897
• 关键词: antineoplastics; biological products; biological signal transduction; calcineurin; cytotoxicity; drug design /synthesis /production; enzyme structure; molecular site; okadaic acid; phosphatase inhibitor; protein binding; protein tyrosine phosphatase

DESCRIPTION: There is a structurally diverse group of natural toxins, includin okadaic acid, calyculin, microcystin LR, and tautomycin, that exert their cytotoxic effects by inhibiting the serine-threonine protein phosphatases PP1 and PP2A. This activity dramatically increases the phosphorylation state of a variety of proteins within the cell, a process that can have profound effects such as the disastrous disruption of intracellular signal trafficking, the deposition of proteinacious plaque and fibrils, and even unregulated cellular proliferation. The compounds themselves are therefore not only acute hepatotoxins, but also tumor promotors. Interestingly, despite the dissimilarities of the toxins structures, these compounds are competitive inhibitors, namely, their PP1/PP2A binding sites overlap. Because as a group they inhibit PP1 and PP2A quite potently and specifically relative to other known phosphatases such as PP2B (calcineurin), PP2C, and the tyrosine phosphatases, several members of this group have become important probes of intracellular signalling pathways. However, there are problems of poor selectivity between the two phosphatases, which can result in ambiguous results when attempts are being made to define the separate roles of PP1 and PP2A in a given process. In particular, there is no known membrane-permeable small molecule that inhibits PP1 with good selectivity. A recently published X-ray crystal structure of a PP1-microcystin LR complex provides a unique opportunity to explore binding interactions of all these inhibitors with both PP1 and PP2A, and to develop new selective inhibitors based on these natural products.

描述：有一组结构不同的天然毒素， 包括冈田酸、盏花素、微囊藻毒素LR和交托霉素，它们对 它们通过抑制丝氨酸-苏氨酸蛋白的细胞毒作用 磷酸酶PP1和PP2A。这一活动大大增加了 细胞内各种蛋白质的磷酸化状态，一个过程 这会产生深远的影响，比如灾难性的破坏 细胞内信号传递，蛋白斑块的沉积和 纤维，甚至不受控制的细胞增殖。这些化合物 因此，它们本身不仅是急性肝毒素，而且是肿瘤 推动者。有趣的是，尽管毒素不同 结构，这些化合物是竞争性抑制剂，即它们的 PP1/PP2A结合位点重叠。 因为作为一个群体，它们非常有效和特异地抑制PP1和PP2A 相对于其他已知的磷酸酶，如PP2B(钙调神经磷酸酶)、PP2C和 酪氨酸磷酸酶，这一组的几个成员已经成为 细胞内信号通路的重要探针。然而，有一些 两种磷酸酶之间选择性差的问题，这可能会导致 在尝试定义独立的 PP1和PP2A在特定过程中的作用。特别是，目前还没有已知的 膜透性小分子，具有良好的选择性抑制PP1。 最近发表的PP1-微囊藻毒素LR络合物的X射线晶体结构 提供了一个独特的机会来探索所有这些 同时含有PP1和PP2A的抑制剂，以及开发新的选择性抑制剂 基于这些天然产物。