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TitleMolecular mechanisms of gating in the calcium-activated chloride channel bestrophin.
Journal, issue, pagesElife, Vol. 8, Year 2019
Publish dateJan 10, 2019
AuthorsAlexandria N Miller / George Vaisey / Stephen B Long /
PubMed AbstractBestrophin (BEST1-4) ligand-gated chloride (Cl) channels are activated by calcium (Ca). Mutation of BEST1 causes retinal disease. Partly because bestrophin channels have no sequence or structural ...Bestrophin (BEST1-4) ligand-gated chloride (Cl) channels are activated by calcium (Ca). 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. Ca 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.
External linksElife / PubMed:30628889 / PubMed Central
MethodsEM (single particle)
Resolution2.7 - 3.1 Å
Structure data

9321

6n23

EMDB-9321, PDB-6n23:
BEST1 in a calcium-bound inactivated state
Method: EM (single particle) / Resolution: 3.1 Å

9322

6n24

EMDB-9322, PDB-6n24:
BEST1 open state W287F mutant, calcium-free
Method: EM (single particle) / Resolution: 3.0 Å

9323

6n25

EMDB-9323, PDB-6n25:
BEST1 open state W287F mutant, calcium-bound
Method: EM (single particle) / Resolution: 2.7 Å

9324

6n26

EMDB-9324, PDB-6n26:
BEST1 calcium-free closed state
Method: EM (single particle) / Resolution: 3.0 Å

9325

6n27

EMDB-9325: BEST1 open state W287F mutant, calcium-bound
PDB-6n27: BEST1 calcium-bound closed state
Method: EM (single particle) / Resolution: 3.0 Å

9326

6n28

EMDB-9326, PDB-6n28:
BEST1 calcium-bound open state
Method: EM (single particle) / Resolution: 2.9 Å

Chemicals

ChemComp-CA:
Unknown entry

Source
  • gallus gallus (chicken)
KeywordsMEMBRANE PROTEIN / ion channel / calcium activated chloride channel / eukaryotic membrane protein / anion channel / transport protein / ligand gated ion channel

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