Aminomethanesulfonic acid illuminates the boundary between full and partial agonists of the pentameric glycine receptor.
Aminomethanesulfonic acid illuminates the boundary between full and partial agonists of the pentameric glycine receptor.
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氨基甲磺酸阐明了五聚甘氨酸受体的全部和部分激动剂之间的边界。
DOI：
10.7554/elife.79148
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发表时间：
2022-08-17
期刊：
影响因子：
7.7
通讯作者：
Sivilotti, Lucia G.
中科院分区：
文献类型：
--
作者：
Ivica, Josip;Zhu, Hongtao;Lape, Remigijus;Gouaux, Eric;Sivilotti, Lucia G.
为了阐明在五聚体配体门控离子通道中激动剂功效的决定因素，我们研究了一种新的化合物，氨基甲磺酸（AMS），一种介于甘氨酸和牛磺酸之间的分子结构中间体。尽管AMS可广泛使用，但迄今为止还没有关于AMS作用于甘氨酸受体的报道，这可能是因为AMS在生理pH下不稳定。在这里，我们发现在pH 5下，AMS是一种有效的激动剂，在斑马鱼α1甘氨酸受体中激发最大单通道打开概率为0.85，远高于β-丙氨酸（0.54）或牛磺酸（0.12），仅次于甘氨酸本身（0.96）。对这些密切相关的激动剂功效的热力学循环分析表明，激动剂分子长度的变化与阴离子部分的大小之间存在超加性相互作用。结合甘氨酸受体的单粒子冷冻电镜结构表明，结合甘氨酸受体的激动剂口袋与甘氨酸一样紧凑，三维分类表明，通道分布在开放和脱敏状态，如甘氨酸，而不是与较弱的部分激动剂β-丙氨酸和牛磺酸相关的封闭中间状态。由于AMS处于完全激动剂和部分激动剂之间，它提供了一个新的工具，帮助我们了解受体激动剂在配体门控离子通道的五聚体超家族中的作用。
To clarify the determinants of agonist efficacy in pentameric ligand-gated ion channels, we examined a new compound, aminomethanesulfonic acid (AMS), a molecule intermediate in structure between glycine and taurine. Despite wide availability, to date there are no reports of AMS action on glycine receptors, perhaps because AMS is unstable at physiological pH. Here, we show that at pH 5, AMS is an efficacious agonist, eliciting in zebrafish α1 glycine receptors a maximum single-channel open probability of 0.85, much greater than that of β-alanine (0.54) or taurine (0.12), and second only to that of glycine itself (0.96). Thermodynamic cycle analysis of the efficacy of these closely related agonists shows supra-additive interaction between changes in the length of the agonist molecule and the size of the anionic moiety. Single particle cryo-electron microscopy structures of AMS-bound glycine receptors show that the AMS-bound agonist pocket is as compact as with glycine, and three-dimensional classification demonstrates that the channel populates the open and the desensitized states, like glycine, but not the closed intermediate state associated with the weaker partial agonists, β-alanine and taurine. Because AMS is on the cusp between full and partial agonists, it provides a new tool to help us understand agonist action in the pentameric superfamily of ligand-gated ion channels.