8qzc | pdb_00008qzc
Structure of calcium-bound mTMEM16A(ac)-L647V/I733V chloride channel at 3.29 A resolution
Structural highlights
FunctionANO1_MOUSE Calcium-activated chloride channel (CaCC) which plays an important role in transepithelial anion transport and smooth muscle contraction. Required for the normal functioning of the interstitial cells of Cajal (ICCs) which generate electrical pacemaker activity in gastrointestinal smooth muscles. Acts as a major contributor to basal and stimulated chloride conductance in airway epithelial cells and plays an important role in tracheal cartilage development.[1] [2] [3] [4] [5] Publication Abstract from PubMedAgonist 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 alpha6 around the Ca(2+) -binding site. The closure of the binding site, which involves the formation of a pi-helix below a hinge region in alpha6, 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. Mechanistic basis of ligand efficacy in the calcium-activated chloride channel TMEM16A.,Lam AK, Dutzler R EMBO J. 2023 Dec 11;42(24):e115030. doi: 10.15252/embj.2023115030. Epub 2023 Nov , 20. PMID:37984335[6] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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