Researchers from the Texas Tech University Health Sciences Center (TTUHSC) have determined the kinetic cycle of a potassium channel at atomic resolution. Potassium channels are important for the normal functioning of the human body. This new study showing, "The Gating Cycle of a K+ Channel at Atomic Resolution." This study was published in eLife.
Ion channels are in every living cell of the human body. They mediate ions transport into and out of the cells to signal many physiological processes. Neurons in the nervous systems rely on ion channels for cell-to-cell communication. Potassium channels are membrane proteins that create an aqueous pore, which is regulated by two internal gates that work in a concerted fashion to allow the flow of potassium ions out of the cells.
The pharmaceutical industry is discovering more potent and safer therapeutic drug molecules with less side effects that can correct potassium channels dysfunction. Potassium channels must open and close to perform their normal physiological function within the human body, but mutations within the human DNA can render a channel always open or closed. This research will allow the creation of new drug molecules that can work as potassium channels openers or inhibitors.
Cuello, along with D. Marien Cortes, also from the TTUHSC Department of Cell Physiology and Molecular Biophysics, and Eduardo Perozo, from the University of Chicago, determined two open state conformations of KcsA, which together with the two previous structures of the closed states from Mackinnon's Laboratory, recapitulate how KcsA moves at atomic resolution. No other lab has ever produced the kinetic cycle of a potassium channel at the atomic level.
In the cellular environment, potassium channels are highly specialized proteins that must adopt different conformations to perform their biological function. These molecules change their conformation in a cyclic fashion always returning to the initial or resting state – this is the kinetic cycle. In this new research article, Cuello and his lab locked open KcsA by engineering disulphide bonds that will hold the channel open and determined two new kinetic intermediate snapshots at very high resolution.
The open-conductive and the open-inactivated states, which together with the existing structures for the C/O (high K+ -structure) and the C/I (low K+ -structure) conformations solved. "We knew if we could trap the channel in action, while in movement, we could have something like a movie depicting the opening and closing of the channel at the atomic level."
We have done the same here but with a molecule and at atomic resolution." KcsA contains two different types of gates, the activation and the inactivation gates. This study shows how they work in a concerted fashion to regulate the flow of potassium ions coming out of the cell."