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Structure paper

TitleIdentification of a drug binding pocket in TMEM16F calcium-activated ion channel and lipid scramblase.
Journal, issue, pagesNat Commun, Vol. 14, Issue 1, Page 4874, Year 2023
Publish dateAug 12, 2023
AuthorsShengjie 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 / Lily Yeh Jan /
PubMed AbstractThe 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 ...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.
External linksNat Commun / PubMed:37573365 / PubMed Central
MethodsEM (single particle)
Resolution3.1 - 3.2 Å
Structure data

40768

8sun

EMDB-40768, PDB-8sun:
TMEM16F 1PBC
Method: EM (single particle) / Resolution: 3.12 Å

40776

8sur

EMDB-40776, PDB-8sur:
TMEM16F bound with Niclosamide
Method: EM (single particle) / Resolution: 3.1 Å

41134

8tag

EMDB-41134, PDB-8tag:
TMEM16F, with Calcium and PIP2, no inhibitor
Method: EM (single particle) / Resolution: 3.2 Å

41136

8tai

EMDB-41136, PDB-8tai:
TMEM16F, with Calcium and PIP2, no inhibitor, Cl2
Method: EM (single particle) / Resolution: 3.1 Å

41137

8tal

EMDB-41137, PDB-8tal:
TMEM16F, with Calcium and PIP2, no inhibitor, Cl1
Method: EM (single particle) / Resolution: 3.2 Å

Chemicals

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose / N-Acetylglucosamine

ChemComp-CA:
Unknown entry

ChemComp-JRF:
1-Hydroxy-3-(trifluoromethyl)pyrido[1,2-a]benzimidazole-4-carbonitrile

ChemComp-VUT:
5-chloro-N-(2-chloro-4-nitrophenyl)-2-hydroxybenzamide

Source
  • mus musculus (house mouse)
KeywordsMEMBRANE PROTEIN / Ca2+-activated ion channels / lipid scramblases / Ca2+-activated ion channels and lipid scramblases / Calcium-activated / ion channels / Calcium-activated ion channels

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