Author/Authors :
Carolin Anders، نويسنده , , Yusuke Higuchi، نويسنده , , Kristin Koschinsky، نويسنده , , Maria Bartel، نويسنده , , Benjamin Schumacher، نويسنده , , Philipp Thiel، نويسنده , , Hajime Nitta، نويسنده , , Regina Preisig-Müller، نويسنده , , Günter Schlichth?rl، نويسنده , , Vijay Renigunta، نويسنده , , Junko Ohkanda، نويسنده , , Jürgen Daut، نويسنده , , Nobuo Kato، نويسنده , , Christian Ottmann، نويسنده ,
Abstract :
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.
