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Journal Article

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

MPS-Authors

Pohjolainen,  Emmi
Department of Theoretical and Computational Biophysics, Max Planck Institute for Multidisciplinary Sciences, Max Planck Society;

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Vaiana,  Andrea C.
Department of Theoretical and Computational Biophysics, Max Planck Institute for Multidisciplinary Sciences, Max Planck Society;

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Grubmüller,  Helmut       
Department of Theoretical and Computational Biophysics, Max Planck Institute for Multidisciplinary Sciences, Max Planck Society;

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Citation

Pan, Y., Pohjolainen, E., Schmidpeter, P. A. M., Vaiana, A. C., Nimigean, C. M., Grubmüller, H., et al. (2023). Discrimination between cyclic nucleotides in a cyclic nucleotide-gated ion channel. Nature Structural and Molecular Biology, 30, 512-520. doi:10.1038/s41594-023-00955-3.


Cite as: https://hdl.handle.net/21.11116/0000-000D-05BC-A
Abstract
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.