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: 6019426
• 负责人: A RICHARD CHAMBERLIN
• 金额: $ 20.91万
• 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/6019426
• 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：有一组结构多样的天然毒素， 包括冈田酸、花萼菌素、微囊藻毒素LR和互变霉素， 它们通过抑制丝氨酸-苏氨酸蛋白的细胞毒性作用 磷酸酶PP 1和PP 2A。 这一活动大大增加了 细胞内各种蛋白质的磷酸化状态， 这可能会产生深远的影响，例如灾难性的破坏， 细胞内信号传递，蛋白质斑块的沉积， 纤维，甚至是不受控制的细胞增殖。 化合物 因此，它们本身不仅是急性肝毒素， 发起人 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 PP 1/PP 2A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PP 1和PP 2A， 相对于其它已知的磷酸酶，如PP 2B（钙调磷酸酶）、PP 2C和 酪氨酸磷酸酶，这一组的几个成员已成为 细胞内信号通路的重要探针。 但有 两种磷酸酶之间选择性差的问题，这可能导致 当试图定义单独的 PP 1和PP 2A在给定过程中的作用。 特别是，没有已知的 具有良好选择性抑制PP 1的膜渗透性小分子。 最近发表的PP 1-微囊藻毒素LR复合物的X射线晶体结构 提供了一个独特的机会来探索所有这些 抑制剂与PP 1和PP 2A，并开发新的选择性抑制剂 基于这些天然产物。