8TAL

TMEM16F, with Calcium and PIP2, no inhibitor, Cl1

Summary for 8TAL

• Entry DOI: 10.2210/pdb8tal/pdb
• EMDB information: 41137
• Descriptor: Anoctamin-6, 2-acetamido-2-deoxy-beta-D-glucopyranose, CALCIUM ION (3 entities in total)
• Functional Keywords: calcium-activated, ion channels, lipid scramblases, membrane protein
• Biological source: Mus musculus (house mouse)
• Total number of polymer chains: 2
• Total formula weight: 193297.29

Authors

Wu, H.,Feng, S.,Cheng, Y. (deposition date: 2023-06-27, release date: 2023-09-06, Last modification date: 2024-10-23)

Primary citation

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

Experimental method

ELECTRON MICROSCOPY (3.2 Å)