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-Structure paper
タイトル | Inhibition mechanism of the chloride channel TMEM16A by the pore blocker 1PBC. |
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ジャーナル・号・ページ | Nat Commun, Vol. 13, Issue 1, Page 2798, Year 2022 |
掲載日 | 2022年5月19日 |
![]() | Andy K M Lam / Sonja Rutz / Raimund Dutzler / ![]() |
PubMed 要旨 | TMEM16A, a calcium-activated chloride channel involved in multiple cellular processes, is a proposed target for diseases such as hypertension, asthma, and cystic fibrosis. Despite these therapeutic ...TMEM16A, a calcium-activated chloride channel involved in multiple cellular processes, is a proposed target for diseases such as hypertension, asthma, and cystic fibrosis. Despite these therapeutic promises, its pharmacology remains poorly understood. Here, we present a cryo-EM structure of TMEM16A in complex with the channel blocker 1PBC and a detailed functional analysis of its inhibition mechanism. A pocket located external to the neck region of the hourglass-shaped pore is responsible for open-channel block by 1PBC and presumably also by its structural analogs. The binding of the blocker stabilizes an open-like conformation of the channel that involves a rearrangement of several pore helices. The expansion of the outer pore enhances blocker sensitivity and enables 1PBC to bind at a site within the transmembrane electric field. Our results define the mechanism of inhibition and gating and will facilitate the design of new, potent TMEM16A modulators. |
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手法 | EM (単粒子) |
解像度 | 2.85 Å |
構造データ | EMDB-14753: Cryo-EM map of 1PBC- and calcium-bound mTMEM16A(ac) chloride channel at 2.85 A resolution |
化合物 | ![]() ChemComp-CA: ![]() ChemComp-JRF: |
由来 |
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![]() | MEMBRANE PROTEIN / calcium-activated chloride channel / anoctamin-1 |