Mechanistic basis of ligand efficacy in the calcium-activated chloride channel TMEM16A.

ABSTRACT: 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 Ca²⁺ -binding site. The closure

SUBMITTER: Lam AK 

PROVIDER: S-EPMC10711664 | biostudies-literature | 2023 Dec

REPOSITORIES: biostudies-literature