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

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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.