G-Protein-Coupled Receptor-Membrane Interactions Depend on the Receptor Activation State
G-Protein-Coupled Receptor-Membrane Interactions Depend on the Receptor Activation State
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DOI：
10.1002/jcc.26082
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发表时间：
2020-02-15
影响因子：
3
通讯作者：
Miao, Yinglong
中科院分区：
文献类型：
--
作者：
Bhattarai, Apurba;Wang, Jinan;Miao, Yinglong
G蛋白偶联受体（GPCR）是人类膜蛋白的最大家族，并且作为目前市售药物的约三分之一的主要靶标。特别是腺苷A（1）受体（A（1）AR）是治疗心脏缺血-再灌注损伤、神经性疼痛和肾脏疾病的重要治疗靶点。作为一种典型的GPCR，A（1）AR位于磷脂膜双层内，通过在不同构象状态之间变化来传递细胞信号。阐明脂质-蛋白质相互作用对于理解GPCR的功能机制具有重要意义。在这里，使用稳健的高斯加速分子动力学（GaMD）方法对非活性（拮抗剂结合）和活性（激动剂和G蛋白结合）A（1）AR进行了全原子模拟，该AR嵌入1-棕榈酰-2-油酰-甘油-3-磷酸胆碱（POPC）脂质双层中。在GaMD模拟中，膜脂在稳定A（1）AR的不同构象状态中起着关键作用。我们的模拟进一步确定了受体的重要区域，这些区域以高度相关的方式与脂质明显相互作用。A（1）AR的激活导致脂质双层的上下小叶中的微分动力学。总之，GaMD增强模拟揭示了依赖于受体激活状态的GPCR和脂质的强耦合动力学。(c)2019 Wiley Periodicals，Inc.
G-protein-coupled receptors (GPCRs) are the largest family of human membrane proteins and serve as primary targets of approximately one-third of currently marketed drugs. In particular, adenosine A(1) receptor (A(1)AR) is an important therapeutic target for treating cardiac ischemia-reperfusion injuries, neuropathic pain, and renal diseases. As a prototypical GPCR, the A(1)AR is located within a phospholipid membrane bilayer and transmits cellular signals by changing between different conformational states. It is important to elucidate the lipid-protein interactions in order to understand the functional mechanism of GPCRs. Here, all-atom simulations using a robust Gaussian accelerated molecular dynamics (GaMD) method were performed on both the inactive (antagonist bound) and active (agonist and G-protein bound) A(1)AR, which was embedded in a 1-palmitoyl-2-oleoyl-glycero-3-phosphocholine (POPC) lipid bilayer. In the GaMD simulations, the membrane lipids played a key role in stabilizing different conformational states of the A(1)AR. Our simulations further identified important regions of the receptor that interacted distinctly with the lipids in highly correlated manner. Activation of the A(1)AR led to differential dynamics in the upper and lower leaflets of the lipid bilayer. In summary, GaMD enhanced simulations have revealed strongly coupled dynamics of the GPCR and lipids that depend on the receptor activation state. (c) 2019 Wiley Periodicals, Inc.