Kowal, JuliaChami, MohamedBaumgartner, PaulArheit, MarcelChiu, Po-LinRangl, MartinaScheuring, SimonSchröder, Gunnar F.Nimigean, Crina M.Stahlberg, Henning2014-08-132014Kowal, Julia, Mohamed Chami, Paul Baumgartner, Marcel Arheit, Po-Lin Chiu, Martina Rangl, Simon Scheuring, Gunnar F. Schröder, Crina M. Nimigean, and Henning Stahlberg. 2014. “Ligand-induced structural changes in the cyclic nucleotide-modulated potassium channel MloK1.” Nature Communications 5 (1): 3106. doi:10.1038/ncomms4106. http://dx.doi.org/10.1038/ncomms4106.2041-1723http://nrs.harvard.edu/urn-3:HUL.InstRepos:12717484Cyclic nucleotide-modulated ion channels are important for signal transduction and pacemaking in eukaryotes. The molecular determinants of ligand gating in these channels are still unknown, mainly because of a lack of direct structural information. Here we report ligand-induced conformational changes in full-length MloK1, a cyclic nucleotide-modulated potassium channel from the bacterium Mesorhizobium loti, analysed by electron crystallography and atomic force microscopy. Upon cAMP binding, the cyclic nucleotide-binding domains move vertically towards the membrane, and directly contact the S1–S4 voltage sensor domains. This is accompanied by a significant shift and tilt of the voltage sensor domain helices. In both states, the inner pore-lining helices are in an ‘open’ conformation. We propose a mechanism in which ligand binding can favour pore opening via a direct interaction between the cyclic nucleotide-binding domains and voltage sensors. This offers a simple mechanistic hypothesis for the coupling between ligand gating and voltage sensing in eukaryotic HCN channels.en-USJournal Article2014-08-1310.1038/ncomms4106