Kunzmann, Patrick ; Krumbach, Jan H. ; Saponaro, Andrea ; Moroni, Anna ; Thiel, Gerhard ; Hamacher, Kay (2024)
Anisotropic network analysis of open/closed HCN4 channel advocates asymmetric subunit cooperativity in cAMP modulation of gating.
In: Journal of chemical information and modeling, 64 (12)
doi: 10.1021/acs.jcim.4c00360
Artikel, Bibliographie
Kurzbeschreibung (Abstract)
Hyperpolarization-activated cyclic nucleotide-modulated (HCN) channels are opened in an allosteric manner by membrane hyperpolarization and cyclic nucleotides such as cAMP. Because of conflicting reports from experimental studies on whether cAMP binding to the four available binding sites in the channel tetramer operates cooperatively in gating, we employ here a computational approach as a promising route to examine ligand-induced conformational changes after binding to individual sites. By combining an elastic network model (ENM) with linear response theory (LRT) for modeling the apo-holo transition of the cyclic nucleotide-binding domain (CNBD) in HCN channels, we observe a distinct pattern of cooperativity matching the "positive-negative-positive" cooperativity reported from functional studies. This cooperativity pattern is highly conserved among HCN subtypes (HCN4, HCN1), but only to a lesser extent visible in structurally related channels, which are only gated by voltage (KAT1) or cyclic nucleotides (TAX4). This suggests an inherent cooperativity between subunits in HCN channels as part of a ligand-triggered gating mechanism in these channels.
Typ des Eintrags: | Artikel |
---|---|
Erschienen: | 2024 |
Autor(en): | Kunzmann, Patrick ; Krumbach, Jan H. ; Saponaro, Andrea ; Moroni, Anna ; Thiel, Gerhard ; Hamacher, Kay |
Art des Eintrags: | Bibliographie |
Titel: | Anisotropic network analysis of open/closed HCN4 channel advocates asymmetric subunit cooperativity in cAMP modulation of gating |
Sprache: | Englisch |
Publikationsjahr: | 3 Juni 2024 |
Ort: | ACS Publications |
Titel der Zeitschrift, Zeitung oder Schriftenreihe: | Journal of chemical information and modeling |
Jahrgang/Volume einer Zeitschrift: | 64 |
(Heft-)Nummer: | 12 |
DOI: | 10.1021/acs.jcim.4c00360 |
Kurzbeschreibung (Abstract): | Hyperpolarization-activated cyclic nucleotide-modulated (HCN) channels are opened in an allosteric manner by membrane hyperpolarization and cyclic nucleotides such as cAMP. Because of conflicting reports from experimental studies on whether cAMP binding to the four available binding sites in the channel tetramer operates cooperatively in gating, we employ here a computational approach as a promising route to examine ligand-induced conformational changes after binding to individual sites. By combining an elastic network model (ENM) with linear response theory (LRT) for modeling the apo-holo transition of the cyclic nucleotide-binding domain (CNBD) in HCN channels, we observe a distinct pattern of cooperativity matching the "positive-negative-positive" cooperativity reported from functional studies. This cooperativity pattern is highly conserved among HCN subtypes (HCN4, HCN1), but only to a lesser extent visible in structurally related channels, which are only gated by voltage (KAT1) or cyclic nucleotides (TAX4). This suggests an inherent cooperativity between subunits in HCN channels as part of a ligand-triggered gating mechanism in these channels. |
ID-Nummer: | pmid:38830626 |
Fachbereich(e)/-gebiet(e): | 10 Fachbereich Biologie 10 Fachbereich Biologie > Biologie der Algen und Protozoen 10 Fachbereich Biologie > Computational Biology and Simulation |
Hinterlegungsdatum: | 10 Jun 2024 11:11 |
Letzte Änderung: | 24 Jun 2024 11:28 |
PPN: | 519008103 |
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