Department of Anesthesiology

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

TitleLigand discrimination and gating in cyclic nucleotide-gated ion channels from apo and partial agonist-bound cryo-EM structures.
Publication TypeJournal Article
Year of Publication2018
AuthorsRheinberger J, Gao X, Schmidpeter PAm, Nimigean CM
JournalElife
Volume7
Date Published2018 07 20
ISSN2050-084X
Abstract

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 single-channel 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.

DOI10.7554/eLife.39775
Alternate JournalElife
PubMed ID30028291
PubMed Central IDPMC6093708
Grant ListP41 GM103310 / GM / NIGMS NIH HHS / United States
R01 GM124451 / GM / NIGMS NIH HHS / United States
R01 GM088352 / GM / NIGMS NIH HHS / United States
R01GM088352 / GM / NIGMS NIH HHS / United States
R01GM124451 and R01GM088352 / GM / NIGMS NIH HHS / United States
R01GM124451 / GM / NIGMS NIH HHS / United States