Atomistic mechanisms of human TRPA1 activation by electrophile irritants through molecular dynamics simulation and mutual information analysis.
Atomistic mechanisms of human TRPA1 activation by electrophile irritants through molecular dynamics simulation and mutual information analysis.
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DOI：
10.1038/s41598-022-08824-7
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发表时间：
2022-03-23
影响因子：
4.6
通讯作者：
Biggin PC
中科院分区：
文献类型：
--
作者：
Habgood M;Seiferth D;Zaki AM;Alibay I;Biggin PC
离子通道TRPA 1是一种混杂的化学传感器，据报道对广谱的有害亲电刺激物以及冷、热和机械感觉有反应。它也与瘙痒和疼痛的发生有关，因此已被研究为新型镇痛药的药物靶点。因此，TRPA 1的亲电活化机制受到广泛关注。TRPA 1结构的孔在开放和关闭状态，以及亲电激动剂的共价结合模式最近已被公布。然而，亲电结合位点和孔之间的耦合的详细机制仍然是推测性的。此外，虽然两个不同的半胱氨酸残基（C621和C665）已被确定为亲电键合和活化的关键，结合的几何形状仅在C621解析。在这里，我们使用分子动力学模拟TRPA 1在开孔和闭孔状态下探索亲电结合位点和孔稳定性之间的变构联系。我们的模拟结果表明，一个开放的孔隙是结构稳定的开放的“口袋”的存在下，在C621/C665区域，但迅速崩溃和关闭时，这些口袋被关闭。亲电体在C621或C665处的结合提供了孔开放状态的稳定化，但在C665处结合的分子被示出能够旋转进出口袋，允许瞬时开放状态的立即稳定化。最后，互信息分析的轨迹揭示了一个信息路径连接亲电结合位点口袋的孔通过电压传感样域，给出了一个详细的洞察孔是如何稳定在开放状态。
The ion channel TRPA1 is a promiscuous chemosensor, with reported response to a wide spectrum of noxious electrophilic irritants, as well as cold, heat, and mechanosensation. It is also implicated in the inception of itch and pain and has hence been investigated as a drug target for novel analgesics. The mechanism of electrophilic activation for TRPA1 is therefore of broad interest. TRPA1 structures with the pore in both open and closed states have recently been published as well as covalent binding modes for electrophile agonists. However, the detailed mechanism of coupling between electrophile binding sites and the pore remains speculative. In addition, while two different cysteine residues (C621 and C665) have been identified as critical for electrophile bonding and activation, the bound geometry has only been resolved at C621. Here, we use molecular dynamics simulations of TRPA1 in both pore-open and pore-closed states to explore the allosteric link between the electrophile binding sites and pore stability. Our simulations reveal that an open pore is structurally stable in the presence of open ‘pockets’ in the C621/C665 region, but rapidly collapses and closes when these pockets are shut. Binding of electrophiles at either C621 or C665 provides stabilisation of the pore-open state, but molecules bound at C665 are shown to be able to rotate in and out of the pocket, allowing for immediate stabilisation of transient open states. Finally, mutual information analysis of trajectories reveals an informational path linking the electrophile binding site pocket to the pore via the voltage-sensing-like domain, giving a detailed insight into the how the pore is stabilized in the open state.
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影响因子：
16.2
作者：
Han Q;Liu D;Convertino M;Wang Z;Jiang C;Kim YH;Luo X;Zhang X;Nackley A;Dokholyan NV;Ji RR
通讯作者：
Ji RR
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作者：
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