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， 包括大田酸、花萼蛋白、微囊藻毒素 LR 和互变霉素， 通过抑制丝氨酸-苏氨酸蛋白发挥细胞毒性作用 磷酸酶 PP1 和 PP2A。 这项活动大大增加了 细胞内多种蛋白质磷酸化状态的一个过程 这可能会产生深远的影响，例如灾难性的破坏 细胞内信号传输、蛋白质斑块的沉积和 原纤维，甚至不受控制的细胞增殖。 化合物 因此它们不仅是急性肝毒素，而且是肿瘤毒素 促销员。 有趣的是，尽管毒素存在差异 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。 因为作为一个整体，它们可以非常有效且特异性地抑制 PP1 和 PP2A 相对于其他已知的磷酸酶，例如 PP2B（钙调神经磷酸酶）、PP2C 和 酪氨酸磷酸酶，该组的几个成员已成为 细胞内信号通路的重要探针。 然而，有 两种磷酸酶之间选择性差的问题，这可能导致 当试图定义单独的结果时，结果不明确 PP1 和 PP2A 在给定进程中的角色。 特别是，目前尚无已知的 膜渗透性小分子，具有良好的选择性抑制 PP1。 最近发表的 PP1-微囊藻毒素 LR 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之间的结合相互作用 PP1和PP2A抑制剂，并开发新的选择性抑制剂 基于这些天然产品。