Microsecond simulations indicate that ethanol binds between subunits and could stabilize an open-state model of a glycine receptor.
Microsecond simulations indicate that ethanol binds between subunits and could stabilize an open-state model of a glycine receptor.
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微秒模拟表明，乙醇在亚基之间结合，可以稳定甘氨酸受体的开放状态模型。
DOI：
10.1016/j.bpj.2011.02.032
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发表时间：
2011
影响因子：
3.4
通讯作者：
Lindahl,Erik
中科院分区：
文献类型：
--
作者：
Murail,Samuel;Wallner,Björn;Trudell,JamesR;Bertaccini,Edward;Lindahl,Erik
Cys-loop受体构成了一个由配体（如乙酰胆碱、血清素、甘氨酸和γ-氨基丁酸）门控的离子通道超家族。所有这些受体被认为具有相同的结构特征，但由于序列的高度变异和有限的结构可用性，我们对变构结合位点的了解仍然有限。这些部位是麻醉剂和酒精分子的常见靶点，具有很高的药理意义。我们采用分子模拟的方法研究了同聚体α1甘氨酸受体（GlyRα1）的乙醇结合和平衡交换，模拟了gloeobacter violaceus五聚体配体门控通道的结构。乙醇具有众所周知的增强作用，可以在高浓度下使用。通过对GlyR进行微秒级模拟，我们能够观察到在腔内的自发结合和平衡配体交换。有趣的是，GlyR跨膜亚基之间和内部似乎都有乙醇结合位点，亚基之间的位置占用率最高，交换最慢（约200 ns）。这个模型位点涉及几个残基，这些残基先前通过突变被鉴定为对增强至关重要。最后，乙醇似乎稳定了GlyR模型，该模型建立在一个可能是开放形式的配体门控通道上。这种稳定性有助于解释变构配体结合在Cys-loop受体中的作用。
Cys-loop receptors constitute a superfamily of ion channels gated by ligands such as acetylcholine, serotonin, glycine, andγ-aminobutyric acid. All of these receptors are thought to share structural characteristics, but due to high sequence variation and limited structure availability, our knowledge about allosteric binding sites is still limited. These sites are frequent targets of anesthetic and alcohol molecules, and are of high pharmacological importance. We used molecular simulations to study ethanol binding and equilibrium exchange for the homomericα1 glycine receptor (GlyRα1), modeled on the structure of theGloeobacter violaceuspentameric ligand-gated channel. Ethanol has a well-known potentiating effect and can be used in high concentrations. By performing two microsecond-scale simulations of GlyR with/without ethanol, we were able to observe spontaneous binding in cavities and equilibrium ligand exchange. Of interest, it appears that there are ethanol-binding sites both between and within the GlyR transmembrane subunits, with the intersubunit site having the highest occupancy and slowest exchange (∼200 ns). This model site involves several residues that were previously identified via mutations as being crucial for potentiation. Finally, ethanol appears to stabilize the GlyR model built on a presumably open form of the ligand-gated channel. This stabilization could help explain the effects of allosteric ligand binding in Cys-loop receptors.