Distinct modulation of calcium-activated chloride channel TMEM16A by drug-binding sites
Year: 2024
Type: article
Abstract: TMEM16A is a calcium-activated chloride channel with significant role in epithelial fluid secretion, sensory transduction, and smooth muscle contraction. Several TMEM16A inhibitors have been identified; however, their binding sites and inhibitory mechanisms remain unclear. Using magnolol and honokiol, the two regioisomeric inhibitors, as chemical probes, we have identified a drug-binding site distinct from the pore region, in TMEM16A, which is described here. With electrophysiology, unbiased molecular docking and clustering, molecular dynamics simulations, and experimental validation with mutant cycle analysis, we show that magnolol and honokiol utilize different drug-binding sites, pore and nonpore pockets. The pore blocker utilizes amino acids crucial for chloride passage, whereas the nonpore blocker allosterically modulates the pore residues to hinder ion permeation. Among 17 inhibitors tested, 11 were pore blockers and 6 were nonpore blockers, indicating the importance of this nonpore pocket. Our study provides insights into drug-binding mechanism in TMEM16A together with a rationale for future drug development.
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: hybrid
Funders: New York Stem Cell Foundation, National Research Foundation, Dongguk University, Kangwon National University, Seoul National University, Sungkyunkwan University, Korea Health Industry Development Institute, National Research Foundation of Korea, Daegu Gyeongbuk Institute of Science and Technology, Ministry of Science and ICT, South Korea
OpenAlex ID: W4405238675