Inhibition mechanism of the chloride channel TMEM16A by the pore blocker 1PBC

Andy K. M. Lam (), Sonja Rutz and Raimund Dutzler ()
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Andy K. M. Lam: University of Zurich
Sonja Rutz: University of Zurich
Raimund Dutzler: University of Zurich

Nature Communications, 2022, vol. 13, issue 1, 1-13

Abstract: Abstract 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.

Date: 2022
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DOI: 10.1038/s41467-022-30479-1

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