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TitleMechanistic basis of ligand efficacy in the calcium-activated chloride channel TMEM16A.
Journal, issue, pagesEMBO J, Vol. 42, Issue 24, Page e115030, Year 2023
Publish dateDec 11, 2023
AuthorsAndy Km Lam / Raimund Dutzler /
PubMed AbstractAgonist 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 ...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 -binding site. The closure of the binding site, which involves the formation of a π-helix below a hinge region in α6, appears to be coupled to the opening of the inner pore gate, thereby governing the channel's open probability and conductance. Our results provide a mechanism for agonist binding and efficacy and a structural basis for the design of potentiators and partial agonists in the TMEM16 family.
External linksEMBO J / PubMed:37984335 / PubMed Central
MethodsEM (single particle)
Resolution3.29 Å
Structure data

18774

8qzc

EMDB-18774: Cryo-EM map of calcium-bound mTMEM16A(ac)-L647V/I733V chloride channel at 3.29 A resolution
PDB-8qzc: Structure of calcium-bound mTMEM16A(ac)-L647V/I733V chloride channel at 3.29 A resolution
Method: EM (single particle) / Resolution: 3.29 Å

Chemicals

ChemComp-CA:
Unknown entry

Source
  • mus musculus (house mouse)
KeywordsMEMBRANE PROTEIN / calcium-activated chloride channel / anoctamin-1

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