蛋白质磷酸酶1（PP1）具有丝氨酸/苏氨酸磷酸酶的活性，广泛参与细胞信号转导过程。来自加利福尼亚大学的Tappan和Chamberlin发现一种小分子物质能够结合该酶的调节位点使其活化，该研究结果以封面论文形式发表于2月22日的《Chemistry & Biology》。
蛋白激酶和蛋白磷酸酶能够使多种蛋白质磷酸化和去磷酸化，从而改变酶、受体和离子通道蛋白质电荷、溶解性和结合能力等，它们广泛参予细胞分裂、基因表达调控、神经信息传递、肌肉收缩和细胞信号转导等重要生命过程中。
蛋白磷酸酶PP1和PP2A活性受损会导致细胞功能障碍，如发生肿瘤、神经元分化异常等，多种调节蛋白能够与其调节部位结合而影响其活性，这些调节蛋白均具有RVXF四肽序列，以往研究发现包含该一致序列的13-300氨基酸多肽仍具有调节蛋白的活性。
研究中，Tappan和Chamberlin采用固相多肽合成和高效液相色谱技术合成并纯化不同长度（包含4-13氨基酸残基）包含RVXF序列的多肽，然后检测其对PP1水解磷酸基团活性的影响，结果发现四肽RVXF即具有识别和活化PP1的活性，它能够结合PP1调节部位使其构象发生变化，同时也能够与内源的PP1抑制物DARPP竞争结合PP1，而去除其抑制作用。
结合之前对于外源PP1抑制剂微囊藻毒素的研究结果，研究人员意外发现，微囊藻毒素中芳香烯烃部分（Adda）及其类似物同样具有活化PP1的功能，其结构与RVXF也有较高的相似程度。这一研究结果将有助于开发非肽类小分子磷酸酶活化药物，降低细胞内磷酸化水平，同蛋白激酶抑制剂一起成为更有效的抗癌药物。
原文出处：
（Chemistry & Biology），Vol 15, 32-42, 167-174, 22 February 2008，Erin Tappan and A. Richard Chamberlin
Activation of Protein Phosphatase 1 by a Small Molecule Designed to Bind to the Enzyme's Regulatory Site
Erin Tappan and A. Richard Chamberlin,
Summary
The activity of protein phosphatase 1 (PP1), a serine-threonine phosphatase that participates ubiquitously in cellular signaling, is controlled by a wide variety of regulatory proteins that interact with PP1 at an allosteric regulatory site that recognizes a “loose” consensus sequence (usually designated as RVXF) found in all such regulatory proteins. Peptides containing the regulatory consensus sequence have been found to recapitulate the binding and PP1 activity modulation of the regulatory proteins, suggesting that it might be possible to design small-molecule surrogates that activate PP1 rather than inhibiting it. This prospect constitutes a largely unexplored way of controlling signaling pathways that could be functionally complementary to the much more extensively explored stratagem of kinase inhibition. Based on these principles, we have designed a microcystin analog that activates PP1.
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