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-Structure paper
タイトル | Identification of a drug binding pocket in TMEM16F calcium-activated ion channel and lipid scramblase. |
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ジャーナル・号・ページ | Nat Commun, Vol. 14, Issue 1, Page 4874, Year 2023 |
掲載日 | 2023年8月12日 |
著者 | 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 / Lily Yeh Jan / |
PubMed 要旨 | 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 ...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. |
リンク | Nat Commun / PubMed:37573365 / PubMed Central |
手法 | EM (単粒子) |
解像度 | 3.1 - 3.2 Å |
構造データ | EMDB-40768, PDB-8sun: EMDB-40776, PDB-8sur: EMDB-41134, PDB-8tag: EMDB-41136, PDB-8tai: EMDB-41137, PDB-8tal: |
化合物 | ChemComp-NAG: ChemComp-CA: ChemComp-JRF: ChemComp-VUT: |
由来 |
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キーワード | MEMBRANE PROTEIN / Ca2+-activated ion channels / lipid scramblases / Ca2+-activated ion channels and lipid scramblases / Calcium-activated / ion channels / Calcium-activated ion channels |