Discrimination between cyclic nucleotides in a cyclic nucleotide-gated ion channel.

TitleDiscrimination between cyclic nucleotides in a cyclic nucleotide-gated ion channel.
Publication TypeJournal Article
Year of Publication2023
AuthorsPan Y, Pohjolainen E, Schmidpeter PAM, Vaiana AC, Nimigean CM, Grubm├╝ller H, Scheuring S
JournalNat Struct Mol Biol
Date Published2023 Apr
KeywordsCyclic AMP, Cyclic GMP, Cyclic Nucleotide-Gated Cation Channels, Ion Channel Gating, Nucleotides, Cyclic

Cyclic nucleotide-gated ion channels are crucial in many physiological processes such as vision and pacemaking in the heart. SthK is a prokaryotic homolog with high sequence and structure similarities to hyperpolarization-activated and cyclic nucleotide-modulated and cyclic nucleotide-gated channels, especially at the level of the cyclic nucleotide binding domains (CNBDs). Functional measurements showed that cyclic adenosine monophosphate (cAMP) is a channel activator while cyclic guanosine monophosphate (cGMP) barely leads to pore opening. Here, using atomic force microscopy single-molecule force spectroscopy and force probe molecular dynamics simulations, we unravel quantitatively and at the atomic level how CNBDs discriminate between cyclic nucleotides. We find that cAMP binds to the SthK CNBD slightly stronger than cGMP and accesses a deep-bound state that a cGMP-bound CNBD cannot reach. We propose that the deep binding of cAMP is the discriminatory state that is essential for cAMP-dependent channel activation.

Alternate JournalNat Struct Mol Biol
PubMed ID36973509
PubMed Central ID6093708
Grant List18POST33960309 / AHA / American Heart Association-American Stroke Association / United States