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

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.

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Item Permalink: https://hdl.handle.net/21.11116/0000-000D-05BC-A Version Permalink: https://hdl.handle.net/21.11116/0000-000D-05BD-9
Genre: Journal Article

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s41594-023-00955-3.pdf (Publisher version), 9MB
 
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2023-03-27
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 Creators:
Pan, Yangang, Author
Pohjolainen, Emmi1, Author
Schmidpeter, Philipp A. M., Author
Vaiana, Andrea C.1, Author           
Nimigean, Crina M., Author
Grubmüller, Helmut1, Author                 
Scheuring, Simon, Author
Affiliations:
1Department of Theoretical and Computational Biophysics, Max Planck Institute for Multidisciplinary Sciences, Max Planck Society, Göttingen, DE, ou_3350132              

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 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.

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Language(s): eng - English
 Dates: 2023-03-272023-04
 Publication Status: Issued
 Pages: -
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 Table of Contents: -
 Rev. Type: Peer
 Identifiers: DOI: 10.1038/s41594-023-00955-3
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Project name : We thank M. Rangl for initial experiments. Work in the Scheuring laboratory was supported by grants from the National Institute of Health, National Center for Complementary and Integrative Health DP1AT010874 and National Institute of Neurological Disorders and Stroke R01NS110790, and by the Kavli Institute at Cornell. Work in the Nimigean laboratory was supported by the National Institute of Health (GM124451 to C.M.N.) and the American Heart Association (18POST33960309 to P.A.M.S.). Work in the Grubmüller laboratory was funded by the Max Planck Society and by the German Science Foundation (DFG), Excellence Strategy Grant MBExC 2067/1-390729940; computer time was provided by the Max Planck Computing and Data Facility. A.C.V. was additionally supported by the European Union’s Horizon 2020 Framework Programme for Research and Innovation, Specific Grant Agreement No. 945539 (Human Brain Project SGA3).
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Project name : HBP SGA3
Grant ID : 945539
Funding program : Horizon 2020 (H2020)
Funding organization : European Commission (EC)

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Title: Nature Structural and Molecular Biology
  Other : Nature Struct Biol
Source Genre: Journal
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Publ. Info: New York, NY : Nature Pub. Group
Pages: - Volume / Issue: 30 Sequence Number: - Start / End Page: 512 - 520 Identifier: ISSN: 1545-9993
CoNE: https://pure.mpg.de/cone/journals/resource/954925603763