Publication

Ligand discrimination and gating in cyclic nucleotide-gated ion channels from apo and partial agonist-bound cryo-EM structures

Rheinberger, J., Gao, X., Schmidpeter, P. A. M. & Nimigean, C. M., 20-Jul-2018, In : eLife. 7, 25 p., 39775.

Research output: Contribution to journalArticleAcademicpeer-review

Cyclic nucleotide-modulated channels have important roles in visual signal transduction and pacemaking. Binding of cyclic nucleotides (cAMP/cGMP) elicits diverse functional responses in different channels within the family despite their high sequence and structure homology. The molecular mechanisms responsible for ligand discrimination and gating are unknown due to lack of correspondence between structural information and functional states. Using single particle cryo-electron microscopy and single-channel recording, we assigned functional states to high-resolution structures of SthK, a prokaryotic cyclic nucleotide-gated channel. The structures for apo, cAMP-bound, and cGMP-bound SthK in lipid nanodiscs, correspond to no, moderate, and low singlechannel activity, respectively, consistent with the observation that all structures are in resting, closed states. The similarity between apo and ligand-bound structures indicates that ligand-binding domains are strongly coupled to pore and SthK gates in an allosteric, concerted fashion. The different orientations of cAMP and cGMP in the 'resting' and 'activated' structures suggest a mechanism for ligand discrimination.

Original languageEnglish
Article number39775
Number of pages25
JournaleLife
Volume7
Publication statusPublished - 20-Jul-2018
Externally publishedYes

    Keywords

  • HCN CHANNELS, K+ CHANNEL, VOLTAGE, BINDING, ACTIVATION, SELECTIVITY, MECHANISMS, MICROSCOPY, RECEPTOR, CAMP

ID: 127135586