8TAI

TMEM16F, with Calcium and PIP2, no inhibitor, Cl2

8TAI の概要

• エントリーDOI: 10.2210/pdb8tai/pdb
• EMDBエントリー: 41136
• 分子名称: Anoctamin-6, 2-acetamido-2-deoxy-beta-D-glucopyranose, CALCIUM ION (3 entities in total)
• 機能のキーワード: calcium-activated ion channels, lipid scramblases, membrane protein
• 由来する生物種: Mus musculus (house mouse)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 193297.29

構造登録者

Wu, H.,Feng, S.,Cheng, Y. (登録日: 2023-06-27, 公開日: 2023-09-06)

主引用文献

Feng, S.,Puchades, C.,Ko, J.,Wu, H.,Chen, Y.,Figueroa, E.E.,Gu, S.,Han, T.W.,Ho, B.,Cheng, T.,Li, J.,Shoichet, B.,Jan, Y.N.,Cheng, Y.,Jan, L.Y.
Identification of a drug binding pocket in TMEM16F calcium-activated ion channel and lipid scramblase.
Nat Commun, 14:4874-4874, 2023

PubMed Abstract: The dual functions of TMEM16F as Ca-activated ion channel and lipid scramblase raise intriguing questions regarding their molecular basis. Intrigued by the ability of the FDA-approved drug niclosamide to inhibit TMEM16F-dependent syncytia formation induced by SARS-CoV-2, we examined cryo-EM structures of TMEM16F with or without bound niclosamide or 1PBC, a known blocker of TMEM16A Ca-activated Cl channel. Here, we report evidence for a lipid scrambling pathway along a groove harboring a lipid trail outside the ion permeation pore. This groove contains the binding pocket for niclosamide and 1PBC. Mutations of two residues in this groove specifically affect lipid scrambling. Whereas mutations of some residues in the binding pocket of niclosamide and 1PBC reduce their inhibition of TMEM16F-mediated Ca influx and PS exposure, other mutations preferentially affect the ability of niclosamide and/or 1PBC to inhibit TMEM16F-mediated PS exposure, providing further support for separate pathways for ion permeation and lipid scrambling.

PubMed: 37573365
DOI: 10.1038/s41467-023-40410-x

実験手法

ELECTRON MICROSCOPY (3.1 Å)