CONUS PEPTIDES AND K CHANNELS

在过去的十年里，钾通道的巨大分子多样性已经变得明显，显然，定义单个分子形式的钾通道的功能将是一个巨大的挑战。在上一次资助期间，我们发现了不同的刀豆肽家族的显著多样性，这些家族显然都是针对K通道的。值得注意的是，每个Conus物种似乎都招募了一个不同的Conus多肽家族来靶向K通道。 我们将系统地探索四个这样的K通道靶向的Conus多肽家族：kappaM-conotoxins、conkunitzins、kappaA-conooxins和I-超家族多肽。 在赠与期的最初阶段，我们将首先关注kappaM-conooxins和conkunitzins，因为以前对这些多肽的表征比其他组更具实质性。虽然KappaA-芋螺毒素和I-超家族多肽具有相当大的潜力，但在系统地鉴定这些多肽之前，必须克服常规化学合成和折叠的重大障碍。在靶向K通道的Conus多肽的不同基团中发现的不同结构框架的惊人多样性，为未来对广泛多样性的Conopteds：K通道复合体的结构-功能研究提供了基础。

The vast molecular diversity of K channels has become apparent in the last decade, and it clearly will be an enormous challenge to define the functions of individual molecular forms of K channels. In the last grant period, we uncovered a remarkable diversity of different conopeptide families all apparently targeted to K channels. Remarkably, each clade of Conus species appears to have recruited a different Conus peptide family to target K channels. We will systematically explore four such K channel-targeted Conus peptide families that have been characterized to very different extents: the kappaM-conotoxins, the conkunitzins, the kappaA-conotoxins and the I-superfamily peptides. In the initial phases of the grant period, we will focus first on the kappaM-conotoxins and conkunitzins since the previous characterization of these peptides has been more substantive than for the other groups. Although there is considerable potential in the kappaA-conotoxins and I-superfamily peptides, significant barriers to routine chemical synthesis and folding have to be overcome before these peptides can be systematically characterized. The surprising diversity of the different structural frameworks found in the divergent groups of Conus peptides that target K channels provides the foundation for future structure-function work on a wide diversity of conopeptide:K channel complexes.