Open AccessMechanism of ligand activation of a eukaryotic cyclic nucleotide−gated channel
Author(s) -
Xiangdong Zheng,
Ziao Fu,
DaiShi Su,
Yuebin Zhang,
Minghui Li,
Yaping Pan,
Huan Li,
Shufang Li,
Robert A. Grassucci,
Zhenning Ren,
Zhengshan Hu,
Xueming Li,
Ming Zhou,
Guohui Li,
Joachim Frank,
Jian Yang
Publication year - 2020
Publication title -
nature structural and molecular biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 9.448
H-Index - 270
eISSN - 1545-9993
pISSN - 1545-9985
DOI - 10.1038/s41594-020-0433-5
Subject(s) - mechanism (biology) , microbiology and biotechnology , chemistry , nucleotide , biophysics , biology , computational biology , genetics , biochemistry , gene , physics , quantum mechanics
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.