Mechanism of ligand activation of a eukaryotic cyclic nucleotide-gated channel
Mechanism of ligand activation of a eukaryotic cyclic nucleotide-gated channel
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真核环核苷酸门控通道的配体激活机制
DOI：
10.1038/s41594-020-0433-5
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发表时间：
2020-06-01
影响因子：
16.8
通讯作者：
Yang，Jian
中科院分区：
文献类型：
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作者：
Zheng，Xiangdong;Fu，Ziao;Yang，Jian
环核苷酸门控（CNG）通道将环核苷酸（CN）结合和未结合转化为感觉受体和神经元中的电信号。支持配体活化的分子构象变化在很大程度上是不确定的。我们报告了在脂质纳米盘中重构的全长秀丽隐杆线虫环GMP激活通道TAX-4的封闭和开放状态原子冷冻EM结构。这些结构，连同计算和功能分析和突变的通道结构，揭示了由两个S6氨基酸在中央腔形成的双屏障疏水门。cGMP结合产生全局构象变化，打开位于~52 nm处的腔门，但不改变选择性过滤器的结构-通常假定的激活门。我们的工作为CN门控和核苷酸调节通道的变构门控和调节以及CNG通道相关的通道病提供了机制见解。
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-lengthCaenorhabditis eleganscyclic 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.