KATP通道激活机制的研究

KATP channel couples cell metabolic status with membrane excitability. It plays important roles in many biological processes, such as regulation of cell membrane potential, neurotransmitter release, insulin secretion etc. The malfunction of KATP leads to many diseases and it is an important drug target. KATP channels are hetero-octameric complexes which are composed of pore-forming Kir6 subunits and regulatory SUR subunits. ATP can bind to Kir6 subunit and inhibit KATP channel activity. Mg-ADP or Mg-ATP can bind to SUR subunit and activate KATP channels. Some clinical drugs can also bind SUR and regulates the gating of KATP channels. Despite of the physiological and clinical importance of KATP channels, the gating mechanism are still largely unknown. Recently, we have made progress on structural study of KATP channel. We will continue to use structural biology methods, together with biochemistry and electrophysiology techniques to solve the structure of KATP channel in complex with Mg-ADP. Combined with functional studies, we will determine the activation mechanism of KATP channel by Mg-ADP.

KATP通道将细胞代谢水平与细胞膜的兴奋性偶联起来，对于神经递质的释放和胰岛素的分泌等众多生物学过程发挥着重要的作用，其功能异常会引发多种疾病，是重要的药物靶点。KATP通道复合体由Kir6亚基和SUR亚基组成，ATP能够结合在Kir6亚基上，抑制KATP通道；而Mg2+结合的核苷酸能够与SUR亚基结合，激活KATP通道；许多药物小分子也能结合在SUR亚基上，调节KATP通道的开关。尽管KATP通道有着如此重要的生理功能和医疗意义，但其激活机制尚不清楚。本课题组目前已在KATP复合体结构研究方面取得一定进展。在此基础上，我们将以结构生物学手段为主，并结合生物化学、电生理等多种技术，通过解析KATP通道与Mg- ADP复合物的结构及相应功能实验来阐明KATP通道的激活机制。

ATP敏感钾离子通道（KATP）可被细胞内ATP抑制，被Mg-ADP激活。KATP开放剂（KCO）是一类在Mg-ATP或Mg-ADP存在下可激活KATP通道的小分子，在临床中应用于治疗高血压、心绞痛和心律失常等心血管疾病。本项目解析了KATP与三种KCO：P1075, Lev, 和NN414复合物的结构，阐明了这些药物的结合方式和激活机制。本项目还阐明了KATP通道被MgADP激活的机制。