Discrimination between cyclic nucleotides in a cyclic nucleotide-gated ion channel.
Journal
Nature structural & molecular biology
ISSN: 1545-9985
Titre abrégé: Nat Struct Mol Biol
Pays: United States
ID NLM: 101186374
Informations de publication
Date de publication:
04 2023
04 2023
Historique:
received:
24
07
2022
accepted:
24
02
2023
medline:
20
4
2023
pubmed:
28
3
2023
entrez:
27
3
2023
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 36973509
doi: 10.1038/s41594-023-00955-3
pii: 10.1038/s41594-023-00955-3
pmc: PMC10194703
mid: NIHMS1889032
doi:
Substances chimiques
Nucleotides, Cyclic
0
Cyclic Nucleotide-Gated Cation Channels
0
Cyclic AMP
E0399OZS9N
Cyclic GMP
H2D2X058MU
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
512-520Subventions
Organisme : American Heart Association-American Stroke Association
ID : 18POST33960309
Pays : United States
Organisme : NCCIH NIH HHS
ID : DP1 AT010874
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM124451
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS110790
Pays : United States
Informations de copyright
© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.
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