Molecular Reorganization During K+ Channel Gating: Determination of Alternate Pore Configurations by X-ray diffraction.

离子通道是一种特殊的小孔，它控制着穿过细胞膜的电荷流动。它们有电活动，可以像电流一样测量。钾通道只允许钾离子通过细胞膜，而不允许其他所有离子进入细胞膜。如果没有钾通道，我们的神经、心脏和其他器官就不会发挥作用。这些通道通过一种天生的能力来调节离子流动，在特定生物信号的要求下打开和关闭，并在生理状态之间轻松切换。影响因素包括去极化脉冲和结合到其表面的小分子，导致毛孔畅通。人类体内存在数百种类型的钾通道，它们可以接受各种暗示。孔洞的结构最近被证实，以四个完全不同的水道的三维模型的形式。这对于阐明离子渗透的各个方面都是非常有价值的。然而，它并没有令人满意地解释是什么导致了毛孔的打开和关闭，它是如何做到的，以及这种机制是否对所有的钾通道都是通用的。相同钾通道的互补模型将允许直接比较结构特征。只有到那时，人们才能证实伴随着开放的分子重排。本项目的实验目的是利用X射线结晶学方法获取此类信息。一种权宜之计是处理已经结晶的四个渠道中的一个，捕获其替代配置。尽管这是一项雄心勃勃的计划，但它有可能带来极大的回报。如果生物物理学界目前的争论水平可以作为衡量标准的话，它也具有无与伦比的科学价值。世界上有很高比例的S药物是针对离子通道的，因为许多疾病都被归因于钾通道活性受损。我们的研究成果将为合理设计新药疗法提供新的依据。

Ion channels are specialised pores that control the flow of charge across cell membranes. They have electrical activity, measurable as current. Potassium channels allow only potassium ions to transit the cell membrane to the exclusion of all others. Without potassium channels our nerves, heart, and other organs, would not function. The channels regulate ion flow by an innate ability to open and close at the behest of specific biological signals, and switch easily between physiological states. Influencing factors include depolarising pulses and small molecules that bind to their surface, causing the pore to unblock. Hundreds of types of potassium channel, receptive to a variety of cues, exist in man. The architecture of the pore has recently been confirmed, in the form of three-dimensional models of four quite different channels. This has been invaluable in elucidating aspects of ion permeation. It has not, however, satisfactorily explained what causes the pore to open and close, how it does so, and if this mechanism is general to all potassium channels. Complementary models of the same potassium channel would permit a direct comparison of structural features. Only then can one verify the molecular rearrangements accompanying opening. The experimental aim of this project is to acquire such information using X-ray crystallographic methods. An expedient approach is to tackle one of the four channels already crystallised, capturing its alternate configuration. Although this is an ambitious plan, it has the potential to be highly rewarding. It is also of unparalleled scientific interest, if the current level of debate in biophysics circles is anything to go by. A high proportion of the world s pharmaceuticals are directed at ion channels, as numerous diseases have been ascribed to compromised potassium channel activity. Our research outcomes will provide a fresh basis for the rational design of new drug therapies.