Publication Date
7-1-2020
Journal
Nature Structural & Molecular Biology
DOI
10.1038/s41594-020-0433-5
PMID
32483338
PMCID
PMC7354226
PubMedCentral® Posted Date
7-27-2020
PubMedCentral® Full Text Version
Post-print
Published Open-Access
yes
Keywords
Caenorhabditis elegans Proteins, Cryoelectron Microscopy, Cyclic GMP, HEK293 Cells, Humans, Hydrophobic and Hydrophilic Interactions, Ion Channels, Ligands, Lipids, Models, Molecular, Molecular Dynamics Simulation, Mutagenesis, Mutation, Protein Conformation
Abstract
Cyclic nucleotide-gated (CNG) channels convert cyclic nucleotide (CN) binding and unbinding into electrical signals in sensory receptors and neurons. The molecular conformational changes underpinning ligand activation are largely undefined. We report both closed- and open-state atomic cryo-EM structures of a full-length Caenorhabditis elegans cyclic GMP-activated channel TAX-4, reconstituted in lipid nanodiscs. These structures, together with computational and functional analyses and a mutant channel structure, reveal a double-barrier hydrophobic gate formed by two S6 amino acids in the central cavity. cGMP binding produces global conformational changes that open the cavity gate located ~52 Å away but do not alter the structure of the selectivity filter-the commonly presumed activation gate. Our work provides mechanistic insights into the allosteric gating and regulation of CN-gated and nucleotide-modulated channels and CNG channel-related channelopathies.
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