%0 Journal Article
%T Atom-by-atom tuning of the electrostatic potassium-channel modulator dehydroabietic acid
%A E. Peter
%A E. Peter M¨¹nger
%A Fredrik Elinder
%A Ingemar
%A Ingemar Lundstr£¿m
%A Konradsson
%A Lundstr£¿m
%A Malin
%A Malin Silver£¿ Ejneby
%A M¨¹nger
%A Nina E.
%A Nina E. Ottosson
%A Ottosson
%A Peter
%A Peter Konradsson
%A Silver£¿ Ejneby
%A Wu
%A Xiongyu
%A Xiongyu Wu
%J JGP | The Journal of General Physiology
%D 2018
%R 10.1085/jgp.201711965
%X Dehydroabietic acid (DHAA) is a naturally occurring component of pine resin that was recently shown to open voltage-gated potassium (KV) channels. The hydrophobic part of DHAA anchors the compound near the channel¡¯s positively charged voltage sensor in a pocket between the channel and the lipid membrane. The negatively charged carboxyl group exerts an electrostatic effect on the channel¡¯s voltage sensor, leading to the channel opening. In this study, we show that the channel-opening effect increases as the length of the carboxyl-group stalk is extended until a critical length of three atoms is reached. Longer stalks render the compounds noneffective. This critical distance is consistent with a simple electrostatic model in which the charge location depends on the stalk length. By combining an effective anchor with the optimal stalk length, we create a compound that opens the human KV7.2/7.3 (M type) potassium channel at a concentration of 1 ¦ÌM. These results suggest that a stalk between the anchor and the effector group is a powerful way of increasing the potency of a channel-opening drug.
%U http://jgp.rupress.org/content/150/5/731