Anders Carolin, Higuchi Yusuke, Koschinsky Kristin, Bartel Maria, Schumacher Benjamin, Thiel Philipp, Nitta Hajime, Preisig-Müller Regina, Schlichthörl Günter, Renigunta Vijay, Ohkanda Junko, Daut Jürgen, Kato Nobuo, Ottmann Christian
Chemical Genomics Centre of the Max-Planck-Society, 44227 Dortmund, Germany.
Chem Biol. 2013 Apr 18;20(4):583-93. doi: 10.1016/j.chembiol.2013.03.015.
Small-molecule stabilization of protein-protein interactions is an emerging field in chemical biology. We show how fusicoccanes, originally identified as fungal toxins acting on plants, promote the interaction of 14-3-3 proteins with the human potassium channel TASK-3 and present a semisynthetic fusicoccane derivative (FC-THF) that targets the 14-3-3 recognition motif (mode 3) in TASK-3. In the presence of FC-THF, the binding of 14-3-3 proteins to TASK-3 was increased 19-fold and protein crystallography provided the atomic details of the effects of FC-THF on this interaction. We also tested the functional effects of FC-THF on TASK channels heterologously expressed in Xenopus oocytes. Incubation with 10 μM FC-THF was found to promote the transport of TASK channels to the cell membrane, leading to a significantly higher density of channels at the surface membrane and increased potassium current.
蛋白质 - 蛋白质相互作用的小分子稳定作用是化学生物学中一个新兴的领域。我们展示了最初被鉴定为作用于植物的真菌毒素的藤壶毒素，如何促进14 - 3 - 3蛋白与人钾通道TASK - 3的相互作用，并提出了一种半合成藤壶毒素衍生物（FC - THF），它靶向TASK - 3中的14 - 3 - 3识别基序（模式3）。在FC - THF存在的情况下，14 - 3 - 3蛋白与TASK - 3的结合增加了19倍，蛋白质晶体学提供了FC - THF对这种相互作用影响的原子细节。我们还测试了FC - THF对非洲爪蟾卵母细胞中异源表达的TASK通道的功能影响。发现用10 μM FC - THF孵育可促进TASK通道向细胞膜的转运，导致表面膜上通道密度显著更高，钾电流增加。
