Ligand-induced structural changes in the cyclic nucleotide-modulated potassium channel MloK1.

TitleLigand-induced structural changes in the cyclic nucleotide-modulated potassium channel MloK1.
Publication TypeJournal Article
Year of Publication2014
AuthorsKowal J, Chami M, Baumgartner P, Arheit M, Chiu P-L, Rangl M, Scheuring S, Schröder GF, Nimigean CM, Stahlberg H
JournalNat Commun
Date Published2014
KeywordsBacterial Proteins, Cryoelectron Microscopy, Crystallography, X-Ray, Cyclic AMP, Ion Channel Gating, Ligands, Mesorhizobium, Microscopy, Atomic Force, Models, Molecular, Potassium Channels

Cyclic 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.

Alternate JournalNat Commun
PubMed ID24469021
PubMed Central IDPMC4086158
Grant ListNIH GM077560 / GM / NIGMS NIH HHS / United States