Probing the control and action of CLIC1/NCC27, an unusual chloride ion channel, by x-ray crystallography

细胞必须调节离子和水在细胞膜上的流动，才能存活并正常运作。离子和水的平衡是由离子通道控制的，离子通道是一种控制细胞膜通透性的蛋白质。在离子通道中，氯离子通道在细胞中最为丰富。它们对正常细胞的功能至关重要，在许多疾病状态中也起着关键作用。我们的小组是第一个识别和表征一类新的氯离子通道，它在免疫系统的调节中起着关键作用。这些通道是不寻常的，因为它们可以在两种状态之间移动：可溶性状态和驻留在细胞膜中的状态。我们已经确定了这类通道在可溶性状态下的第一个结构。在这个项目中，我们将确定：蛋白质如何过渡到膜状态；哪些因素控制了这种转变？以及膜状态下蛋白质的结构。我们还将确定几种药物如何控制该通道的活性。我们的工作结果将对我们的通道产生特定的影响，并将作为这种新型氯化物通道的其他成员的范例。了解这种通道的功能以及目前的药物是如何控制它的，将有助于开发出一类新的治疗药物，通过阻止这些通道从可溶性状态过渡到膜状态来控制这些通道。

Cells must regulate the flow of ions and water across their membranes in order to survive and function normally. The balance of ions and water is controlled by ion channels - proteins that control the permeability of the cell membrane. Of the ion channels, chloride channels are the most abundant in cells. They are central to the functioning of normal cells as well as playing a key role in many disease states. Our group was the first to identify and characterise a new class of chloride channel which plays a key roles in the regulation of the immune system. These channels are unusual in that they can move between two states: a soluble state and a state that resides in the cell membrane. We have determined the first structure of this class of channel in the soluble state. In this project, we will determine: how the protein makes the transition into the membrane state; which factors control this transition; and the structure of the protein in the membrane state. We will also determine how several drugs control the activity of this channel. The results of our work will have specific implications for our channel and will serve as a paradigm for other members of this new class of chloride channel. Understanding how this channel functions and how the current drugs control it will lead to the development of a new class of therapeutic agents that will control these channels by preventing the transition from the soluble to the membrane state.