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Elife. 2019 Jan 10;8. pii: e43231. doi: 10.7554/eLife.43231.

Molecular mechanisms of gating in the calcium-activated chloride channel bestrophin.

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Structural Biology Program, Memorial Sloan Kettering Cancer Center, New York, United States.
Louis V. Gerstner Jr. Graduate School of Biomedical Sciences, Memorial Sloan Kettering Cancer Center, New York, United States.
Contributed equally


Bestrophin (BEST1-4) ligand-gated chloride (Cl-) channels are activated by calcium (Ca2+). Mutation of BEST1 causes retinal disease. Partly because bestrophin channels have no sequence or structural similarity to other ion channels, the molecular mechanisms underlying gating are unknown. Here, we present a series of cryo-electron microscopy structures of chicken BEST1, determined at 3.1 Å resolution or better, that represent the channel's principal gating states. Unlike other channels, opening of the pore is due to the repositioning of tethered pore-lining helices within a surrounding protein shell that dramatically widens a neck of the pore through a concertina of amino acid rearrangements. The neck serves as both the activation and the inactivation gate. Ca2+ binding instigates opening of the neck through allosteric means whereas inactivation peptide binding induces closing. An aperture within the otherwise wide pore controls anion permeability. The studies define a new molecular paradigm for gating among ligand-gated ion channels.


allosteric mechanisms; anion channel; biochemistry; calcium-activated chloride channels; chemical biology; electrophysiology; gating; ion channels; molecular biophysics; none; structural biology

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