Lateral access mechanism of LPA receptor probed by molecular dynamics simulation.
Lateral access mechanism of LPA receptor probed by molecular dynamics simulation.
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DOI：
10.1371/journal.pone.0263296
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发表时间：
2022
期刊：
影响因子：
3.7
通讯作者：
Nureki O
中科院分区：
文献类型：
--
作者：
Suenaga R;Takemoto M;Inoue A;Ishitani R;Nureki O
G蛋白偶联受体（GPCR）是一类在多种生理现象的调节中发挥重要作用的膜受体家族。LPA受体（LPA 1 -6）是A类GPCR的成员，其传递溶血磷脂酸（LPA）信号穿过细胞膜并引起各种反应，包括细胞存活、增殖、分化和迁移。LPA 6的晶体结构揭示了其跨膜螺旋（TM）之间的间隙，该间隙朝向膜侧开放。这导致了“侧向进入模型”的提出，在该模型中，其亲脂性配体通过膜上的差距结构直接进入结合口袋。在这项研究中，我们进行了分子动力学（MD）模拟和马尔可夫状态模型（MSM）分析LPA 6和LPA，阐明配体结合过程的长时间尺度动力学。71.4 μs的分子动力学模拟结果表明，构成差距结构的TM的柔性使配体能够侧向进入，受体与配体之间的关键相互作用促进了配体结合过程的过渡态.
G-protein-coupled receptors (GPCR) are a family of membrane receptors that play important roles in the regulation of various physiological phenomena. LPA receptors (LPA1-6) are members of the class A GPCRs, which transduce a lysophosphatidic acid (LPA) signal across the cell membrane and evoke various responses, including cellular survival, proliferation, differentiation, and migration. The crystal structure of LPA6 revealed a gap between its transmembrane helices (TMs), which is opened toward the membrane side. This led to the proposal of the “lateral access model,” in which its lipophilic ligand directly enters the binding pocket through the gap structure at the membrane. In this study, we performed molecular dynamics (MD) simulations and Markov state model (MSM) analyses of LPA6 and LPA, to elucidate the long timescale dynamics of the ligand binding process. The results from the 71.4-μs MD simulation suggested that the flexibility of the TMs constituting the gap structure enables the lateral entrance of the ligand, and the key interactions between the receptor and ligand facilitate the transition state of the ligand binding process.
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