8QZC

Structure of calcium-bound mTMEM16A(ac)-L647V/I733V chloride channel at 3.29 A resolution

Summary for 8QZC

• Entry DOI: 10.2210/pdb8qzc/pdb
• EMDB information: 18774
• Descriptor: Anoctamin-1, CALCIUM ION (2 entities in total)
• Functional Keywords: calcium-activated chloride channel, anoctamin-1, membrane protein
• Biological source: Mus musculus (house mouse)
• Total number of polymer chains: 2
• Total formula weight: 222222.20

Authors

Lam, A.K.M.,Dutzler, R. (deposition date: 2023-10-26, release date: 2023-12-06, Last modification date: 2024-10-23)

Primary citation

Lam, A.K.,Dutzler, R.
Mechanistic basis of ligand efficacy in the calcium-activated chloride channel TMEM16A.
Embo J., 42:e115030-e115030, 2023

PubMed 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 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.

PubMed: 37984335
DOI: 10.15252/embj.2023115030

Experimental method

ELECTRON MICROSCOPY (3.29 Å)