The molecular basis for an allosteric inhibition of K+-flux gating in K2P channels
The molecular basis for an allosteric inhibition of K+-flux gating in K2P channels
复制标题
K2P 通道 K 流门控变构抑制的分子基础
作者：
S. Rinné;Aytuğ K. Kiper;Kirsty S. Vowinkel;D. Ramírez;Marcus Schewe;M. Bedoya;Diana Aser;Isabella Gensler;Michael F. Netter;P. Stansfeld;T. Baukrowitz;W. González;N. Decher
双孔结构域钾离子通道（Two-pore-domain potassium channels，K2 P）是许多生理和病理生理过程的关键调节因子，因此成为一种有前途的药物靶点。至于其他钾通道，缺乏选择性阻断剂，因为药物优先结合位于中央腔的保守结合位点。因此，有一个高度的医学需要，以确定新的药物结合位点以外的保守的亲脂性中央腔，并确定新的变构机制的通道抑制。在这里，我们确定了一种新的结合位点和变构抑制机制，破坏了最近提出的K+通量门控机制的K2 P通道，这导致了一个不寻常的电压依赖性阻断泄漏通道属于的任务亚家族。新的结合位点和抑制的变构机制提供了对ASK通道门控的结构和机制的见解，以及针对特定类型的K2 P通道的新型强效阻断剂的药物设计的基础。
Two-pore-domain potassium (K2P) channels are key regulators of many physiological and pathophysiological processes and thus emerged as promising drug targets. As for other potassium channels, there is a lack of selective blockers, since drugs preferentially bind to a conserved binding site located in the central cavity. Thus, there is a high medical need to identify novel drug-binding sites outside the conserved lipophilic central cavity and to identify new allosteric mechanisms of channel inhibition. Here, we identified a novel binding site and allosteric inhibition mechanism, disrupting the recently proposed K+-flux gating mechanism of K2P channels, which results in an unusual voltage-dependent block of leak channels belonging to the TASK subfamily. The new binding site and allosteric mechanism of inhibition provide structural and mechanistic insights into the gating of TASK channels and the basis for the drug design of a new class of potent blockers targeting specific types of K2P channels.
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影响因子：
7.3
作者：
Sherman, W;Day, T;Farid, R
通讯作者：
Farid, R
影响因子：
7.3
作者：
Halgren, TA;Murphy, RB;Banks, JL
通讯作者：
Banks, JL
影响因子：
3.4
作者：
Kutluay, E;Roux, B;Heginbotham, L
通讯作者：
Heginbotham, L
影响因子：
3.4
作者：
Brennecke, Julian T.;de Groot, Bert L.
通讯作者：
de Groot, Bert L.
影响因子：
7.3
作者：
Friesner, RA;Banks, JL;Shenkin, PS
通讯作者：
Shenkin, PS