3-dimensional structure and function of SthK, a prokaryote cyclic nucleotide-gated ion channel.

Cyclic nucleotide-modulated ion channels are molecular electric switches that open in response to binding of cyclic AMP or cyclic GMP, which are universal second messengers. The human genome encodes two different classes of cyclic nucleotide-modulated ion channels, namely the cyclic nucleotide-gated (CNG) ion channels and the hyperpolarization-activated cyclic nucleotide-sensitive (HCN) ion channels. Both classes of ion channels have a fundamental role in signal transduction as well as in human health and disease. Detailed insight into the mechanism of coupling between ligand binding and channel opening is currently lacking. In this study, we take advantage of SthK, a prokaryote cyclic nucleotide-gated K+ channel, as a model to understand human CNG and HCN channel gating. SthK originates from an extremophile micro-organism, making it a highly attractive target for structural studies. We will employ a hybrid approach based on X-ray crystallography and cryo-electron microscopy to determine structures of SthK both in the unliganded resting state and the liganded open state. We expect that our results will reveal the mechanism of channel gating, ion permeation and ligand recognition. In combination with electrophysiological recordings we will relate structure to function and pave the way for the structure-based development of new drugs that can better treat channel-related disorders.