State-dependent protein-lipid interactions of a pentameric ligand-gated ion channel in a neuronal membrane.
State-dependent protein-lipid interactions of a pentameric ligand-gated ion channel in a neuronal membrane.
复制标题
神经元膜中五聚体配体门控离子通道的状态依赖性蛋白质-脂质相互作用。
DOI：
10.1371/journal.pcbi.1007856
复制
发表时间：
2021-03
影响因子：
4.3
通讯作者：
Biggin PC
中科院分区：
文献类型：
--
作者：
Dämgen MA;Biggin PC
五聚体配体门控离子通道（pLGIC）是对其膜环境敏感的受体蛋白，但脂质如何在生理条件下以状态依赖性方式调节功能的机制尚不清楚。甘氨酸受体是一种pLGIC，其结构已被解析为不同的功能状态。使用一个现实的模型与粗粒度的分子动力学模拟耦合的神经元膜，我们证明了一些关键的脂质-蛋白质相互作用依赖于受体的状态，这表明脂质可以调节受体的构象动力学。与现有结构数据的比较证实了已知的脂质结合位点，但我们也预测进一步的蛋白质-脂质相互作用，包括在细胞外和跨膜结构域之间的通信接口的网站。此外，在活性状态下，胆固醇可以结合到正变构调节剂伊维菌素的结合位点。这些蛋白质-脂质相互作用位点将来可用于脂质样变构药物的合理设计。离子通道是控制离子流入细胞的蛋白质。被称为五聚体配体门控离子通道（pLGICS）的离子通道家族响应于神经递质的结合而打开，将通道从静息状态移动到打开状态。甘氨酸受体是一种pLGIC，其结构已被解析为不同的功能状态。还已知pLGIC的反应也可以被膜本身内发现的不同类型的脂质修饰，但具体如何修饰尚不清楚。在这里，我们使用了一个现实的神经元膜模型，并进行了分子动力学模拟，以显示依赖于通道状态的各种脂质-蛋白质相互作用。我们的工作还揭示了以前未被考虑的蛋白质-脂质相互作用在一个关键的连接点的通道已知是至关重要的开放过程的传输。我们还证明，胆固醇与蛋白质在一个已知的位点相互作用，结合到另一种化合物，调节通道，称为伊维菌素。这一工作对今后设计变构调节剂具有一定的指导意义。
Pentameric ligand-gated ion channels (pLGICs) are receptor proteins that are sensitive to their membrane environment, but the mechanism for how lipids modulate function under physiological conditions in a state dependent manner is not known. The glycine receptor is a pLGIC whose structure has been resolved in different functional states. Using a realistic model of a neuronal membrane coupled with coarse-grained molecular dynamics simulations, we demonstrate that some key lipid-protein interactions are dependent on the receptor state, suggesting that lipids may regulate the receptor’s conformational dynamics. Comparison with existing structural data confirms known lipid binding sites, but we also predict further protein-lipid interactions including a site at the communication interface between the extracellular and transmembrane domain. Moreover, in the active state, cholesterol can bind to the binding site of the positive allosteric modulator ivermectin. These protein-lipid interaction sites could in future be exploited for the rational design of lipid-like allosteric drugs. Ion channels are proteins that control the flow of ions into the cell. The family of ion channels known as the pentameric ligand gated ion channels (pLGICS) open in response to the binding of a neurotransmitter, moving the channel from a resting state to an open state. The glycine receptor is a pLGIC whose structure has been resolved in different functional states. It is also known that the response of pLGICs can also be modified by different types of lipids found within the membrane itself but exactly how is unclear. Here, we used a realistic model of a neuronal membrane and performed molecular dynamics simulations to show various lipid-protein interactions that are dependent on the channel state. Our work also reveals previously unconsidered protein-lipid interactions at a key junction of the channel known to be critical for the transmission of the opening process. We also demonstrate that cholesterol interacts with the protein at a site already known to bind to another compound that modulates the channel, called ivermectin. The work should be useful for future design of allosteric modulators.
登录
查看更多内容
影响因子：
3.3
作者：
Cheng, Mary H.;Xu, Yan;Tang, Pei
通讯作者：
Tang, Pei
影响因子：
5.5
作者：
de Jong, Djurre H.;Singh, Gurpreet;Marrink, Siewert J.
通讯作者：
Marrink, Siewert J.
影响因子：
6.3
作者：
de Jong, Djurre H.;Baoukina, Svetlana;Marrink, Siewert J.
通讯作者：
Marrink, Siewert J.
影响因子：
2.9
作者：
CRIADO, M;EIBL, H;BARRANTES, FJ
通讯作者：
BARRANTES, FJ
影响因子：
14.9
作者：
Benkert P;Künzli M;Schwede T
通讯作者：
Schwede T