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

Yangang Pan, Emmi Pohjolainen, Philipp A M Schmidpeter, Andrea C Vaiana, Crina M Nimigean, Helmut Grubmüller, Simon Scheuring

Nature structural & molecular biology 2023 Apr

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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. © 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.

Citation

Yangang Pan, Emmi Pohjolainen, Philipp A M Schmidpeter, Andrea C Vaiana, Crina M Nimigean, Helmut Grubmüller, Simon Scheuring. Discrimination between cyclic nucleotides in a cyclic nucleotide-gated ion channel. Nature structural & molecular biology. 2023 Apr;30(4):512-520