Identification of a drug binding pocket in TMEM16F calcium-activated ion channel and lipid scramblase

Shengjie Feng, Cristina Puchades, Juyeon Ko, Hao Wu, Yifei Chen, Eric E. Figueroa, Shuo Gu, Tina W. Han, Brandon Ho, Tong Cheng, Junrui Li, Brian Shoichet, Yuh Nung Jan, Yifan Cheng () and Lily Yeh Jan ()
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Shengjie Feng: University of California San Francisco (UCSF) School of Medicine
Cristina Puchades: University of California San Francisco (UCSF) School of Medicine
Juyeon Ko: University of California San Francisco (UCSF) School of Medicine
Hao Wu: University of California San Francisco (UCSF) School of Medicine
Yifei Chen: Howard Hughes Medical Institute; UCSF
Eric E. Figueroa: University of California San Francisco (UCSF) School of Medicine
Shuo Gu: BioDuro-Sundia Inc.
Tina W. Han: University of California San Francisco (UCSF) School of Medicine
Brandon Ho: University of California San Francisco (UCSF) School of Medicine
Tong Cheng: Howard Hughes Medical Institute; UCSF
Junrui Li: University of California San Francisco (UCSF) School of Medicine
Brian Shoichet: University of California San Francisco (UCSF) School of Pharmacy
Yuh Nung Jan: University of California San Francisco (UCSF) School of Medicine
Yifan Cheng: University of California San Francisco (UCSF) School of Medicine
Lily Yeh Jan: University of California San Francisco (UCSF) School of Medicine

Nature Communications, 2023, vol. 14, issue 1, 1-12

Abstract: Abstract The dual functions of TMEM16F as Ca2+-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 Ca2+-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 Ca2+ 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.

Date: 2023
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DOI: 10.1038/s41467-023-40410-x

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