Selective inhibition of calcineurin-NFAT signaling by blocking protein-protein interaction with small organic molecules
Selective inhibition of calcineurin-NFAT signaling by blocking protein-protein interaction with small organic molecules
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DOI：
10.1073/pnas.0401835101
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发表时间：
2004-05-18
影响因子：
11.1
通讯作者：
Hogan, PG
中科院分区：
文献类型：
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作者：
Roehrl, MHA;Kang, SH;Hogan, PG
瞬时或可逆的蛋白质-蛋白质相互作用通常用于确保信号酶有效靶向其细胞底物。这些相互作用包括与底物的直接结合、与辅助蛋白或支架蛋白的相互作用以及定位在靠近底物的亚细胞位置。专门靶向机制的存在提高了设计抑制剂的可能性，这些抑制剂本身不阻断酶活性，而是干扰酶靶向细胞内的一种或多种底物。在这里，我们鉴定了可特异性阻断蛋白磷酸酶钙调神经磷酸酶靶向活化 T 细胞的底物核因子（NFAT，也称为 NFATc）的有机小分子，并表明它们是钙调神经磷酸酶-NFAT 信号传导的有效抑制剂。
Transient or reversible protein-protein interactions are commonly used to ensure efficient targeting of signaling enzymes to their cellular substrates. These interactions include direct binding to substrate, interaction with an accessory or scaffold protein, and positioning at subcellular locations in proximity to substrates. The existence of specialized targeting mechanisms raises the possibility of designing inhibitors that do not block enzyme activity per se, but rather interfere with targeting of the enzyme to one or more of its substrates within the cell. Here, we identify small organic molecules that specifically block targeting of the protein phosphatase calcineurin to its substrate nuclear factor of activated T cells (NFAT, also termed NFATc) and show that they are effective inhibitors of calcineurin-NFAT signaling.