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JBC RESEARCH ARTICLE

发布日期:2021-09-27 16:52:23 【关闭】
摘要:Natural product monomers purchased from Chengdu DeSiTe Biological Technology Co, Ltd.
Theaflflavin binds to a druggable pocket of TMEM16A channeland inhibits lung adenocarcinoma cell viability
 
Received for publication, April 26, 2021, and in revised form, July 22, 2021 Published, Papers in Press, July 28, 2021,
https://doi.org/10.1016/j.jbc.2021.101016
 

ABSTRACT

As a calcium-activated chloride channel regulated by the intracellular Ca2+ concentration and membrane potential,TMEM16A has attracted considerable attention and has been proposed as a novel anticancer drug target. We have previously
reported that the pocket above the ion conductance pore could be a nonselective inhibitor-binding pocket. However, whether this pocket is druggable remains unexplored. In this study, we performed virtual screening to target the presumed inhibitor-binding pocket and identifified a highly effective TMEM16A inhibitor, theaflflavin (TF: a tea polyphenol in black tea). Mo-lecular dynamics simulations revealed that theaflflavin adopts a“wedge insertion mode” to block the ion conduction pore and induces pore closure. Moreover, the binding mode showed that the TF pedestal plays an important role in pore blockade, and R515, R535, T539, K603, E623, and E633 were determined to be most likely to interact directly with the pedestal. Mutagenesis experiment results corroborated the mechanism through which TF binds to this pocket. Combined with the quantitative calculation results, our data indicated that the three hydroxyl groups on the pedestal may be the most crucial pharmaco-phores for TMEM16A inhibition by TF. Finally, antitumor experiments revealed that TF could target TMEM16A to inhibit the proliferation and migration of LA795 cells, indi-cating the potential therapeutic effect of TF on the growth of lung adenocarcinoma with high TMEM16A expression. The successful application of drug screening strategies based on this binding pocket highlights new directions for discovering su-perior modulators and contributes to the development of novel therapeutics for lung adenocarcinoma.


Natural product monomers purchased from Chengdu DeSiTe Biological Technology Co, Ltd.


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