Modulation of TRPV2 by endogenous and exogenous ligands: A computational study
Modulation of TRPV2 by endogenous and exogenous ligands: A computational study
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DOI：
10.1002/pro.4490
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发表时间：
2023-01-01
期刊：
影响因子：
8
通讯作者：
Im, Wonpil
中科院分区：
文献类型：
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作者：
Feng, Shasha;Pumroy, Ruth A.;Im, Wonpil
瞬时受体电位香草酸（TRPV）通道在人体生理学中起着重要的作用.作为膜蛋白，这些通道是由其内源性脂质环境调节的，因为最近丰富的结构研究揭示了功能和结构脂质结合位点。此外，已经表明外源配体可以与这些脂质中的一些交换以改变通道门控。在这里，我们使用分子动力学模拟来研究TRPV家族的一个成员TRPV 2如何与内源性脂质和药理学调节剂大麻二酚（CBD）相互作用。通过计算重建TRPV 2到一个典型的质膜环境，其中包括磷脂，胆固醇，磷脂酰肌醇（PIP）的内部小叶，我们发现，大多数相互作用的表面脂质磷脂没有很强的特异性头基类型。有趣的是，我们观察到通道的C-末端膜近端区域优先与PIP脂质结合。我们还模拟了两种结构脂质：一种在香草素口袋里，另一种在电压传感器样结构域（VSLD）口袋里。模拟结果表明，VSLD脂质抑制VSLD残基的波动，而香草素脂质表现出异质性，无论是在其结合姿态和其对蛋白质动力学的影响。添加CBD到我们的模拟系统导致了开放的选择性过滤器和结构重排，包括锚蛋白重复结构域，TRP螺旋和VSLD的顺时针旋转。总之，这些结果揭示了内源性脂质和外源性配体之间的相互作用及其对TRPV 2稳定性和通道门控的影响。
Transient receptor potential vanilloid (TRPV) channels play various important roles in human physiology. As membrane proteins, these channels are modulated by their endogenous lipid environment as the recent wealth of structural studies has revealed functional and structural lipid binding sites. Additionally, it has been shown that exogenous ligands can exchange with some of these lipids to alter channel gating. Here, we used molecular dynamics simulations to examine how one member of the TRPV family, TRPV2, interacts with endogenous lipids and the pharmacological modulator cannabidiol (CBD). By computationally reconstituting TRPV2 into a typical plasma membrane environment, which includes phospholipids, cholesterol, and phosphatidylinositol (PIP) in the inner leaflet, we showed that most of the interacting surface lipids are phospholipids without strong specificity for headgroup types. Intriguingly, we observed that the C-terminal membrane proximal region of the channel binds preferentially to PIP lipids. We also modelled two structural lipids in the simulation: one in the vanilloid pocket and the other in the voltage sensor-like domain (VSLD) pocket. The simulation shows that the VSLD lipid dampens the fluctuation of the VSLD residues, while the vanilloid lipid exhibits heterogeneity both in its binding pose and in its influence on protein dynamics. Addition of CBD to our simulation system led to an open selectivity filter and a structural rearrangement that includes a clockwise rotation of the ankyrin repeat domains, TRP helix, and VSLD. Together, these results reveal the interplay between endogenous lipids and an exogenous ligand and their effect on TRPV2 stability and channel gating.