Mechanistic basis of ligand efficacy in the calcium-activated chloride channel TMEM16A.
chloride channel
cryo-electron microscopy
efficacy
electrophysiology
ligand gating
Journal
The EMBO journal
ISSN: 1460-2075
Titre abrégé: EMBO J
Pays: England
ID NLM: 8208664
Informations de publication
Date de publication:
11 Dec 2023
11 Dec 2023
Historique:
revised:
27
10
2023
received:
19
07
2023
accepted:
02
11
2023
pubmed:
21
11
2023
medline:
21
11
2023
entrez:
20
11
2023
Statut:
ppublish
Résumé
Agonist binding in ligand-gated ion channels is coupled to structural rearrangements around the binding site, followed by the opening of the channel pore. In this process, agonist efficacy describes the equilibrium between open and closed conformations in a fully ligand-bound state. Calcium-activated chloride channels in the TMEM16 family are important sensors of intracellular calcium signals and are targets for pharmacological modulators, yet a mechanistic understanding of agonist efficacy has remained elusive. Using a combination of cryo-electron microscopy, electrophysiology, and autocorrelation analysis, we now show that agonist efficacy in the ligand-gated channel TMEM16A is dictated by the conformation of the pore-lining helix α6 around the Ca
Identifiants
pubmed: 37984335
doi: 10.15252/embj.2023115030
pmc: PMC10711664
doi:
Banques de données
PDB
['8QZC']
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
e115030Subventions
Organisme : EC | FP7 | Ideas | FP7 Ideas: European Research Council (IDEE-CER)
ID : 339116
Organisme : Novartis Foundation for Medical-Biological Research
Organisme : University of Zurich Forschungskredit
ID : FK-18-048
Informations de copyright
© 2023 The Authors. Published under the terms of the CC BY 4.0 license.
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