S1P结合和S1P1受体激活的分子机制。,Journal of Chemical Information and Modeling

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S1P结合和S1P1受体激活的分子机制。
Journal of Chemical Information and Modeling ( IF 5.6 ) Pub Date : 2019-10-15 , DOI: 10.1021/acs.jcim.9b00642
Zhenyan Jiang , Hansi Zhang

1-磷酸鞘氨醇（S1P）是哺乳动物中的脂质介体，可充当第二信使或配体。在后一种情况下，它通过与HDL相关的apoM载体运输并在血液中循环，在血液中与细胞膜上的特定S1P受体结合并诱导下游反应。尽管S1P信号通路对于许多生物学过程至关重要，但在分子水平上却了解甚少。在这里，已解决的S1P1受体的晶体结构用于评估分子动力学（MD）模拟，以产生更详细的分子信息，以了解S1P信号传导的机制。MD模拟提供了在粗粒度和原子水平的观察结果，表明S1P可能直接从溶剂进入受体结合袋。受体的笨重的N末端帽区域的抬起先于初始S1P结合。Glu1213.29指导S1P的渗透，并与Arg2927.34一起负责结合口袋中S1P的稳定化，这与实验预测是一致的。S1P的完全结合之后是受体激活，其中Trp2696.48向着跨膜螺旋（TM）7移动，导致在TM7的下部区域形成增强的氢键网络。随后增加了TM3和TM6之间的距离，从而打开了使G蛋白结合的胞内结合袋。对受体中的力分布网络的进一步分析对激动剂结合后激活的信号传输网络产生了详细的分子理解。

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Molecular Mechanism of S1P Binding and Activation of the S1P1 Receptor.

Sphingosine-1-phosphate (S1P) is a lipidic mediator in mammals that functions either as a second messenger or as a ligand. In the latter case, it is transported by its HDL-associated apoM carrier and circulated in blood where it binds to specific S1P receptors on cell membranes and induces downstream reactions. Although S1P signaling pathways are essential for many biological processes, they are poorly understood at the molecular level. Here, the solved crystal structures of the S1P1 receptor were used to evaluate molecular dynamics (MD) simulations to generate greater detailed molecular insights into the mechanism of S1P signaling. The MD simulations provided observations at the coarse-grained and atomic levels indicating that S1P may access the receptor binding pocket directly from solvents. Lifting of the bulky N-terminal cap region of the receptor precedes initial S1P binding. Glu1213.29 guides S1P penetration, and together with Arg2927.34 is responsible for the stabilization of S1P in the binding pocket, which is consistent with experimental predictions. The complete binding of S1P is followed by receptor activation, wherein Trp2696.48 moves toward the transmembrane helix (TM) 7, resulting in the formation of an enhanced hydrogen bond network in the lower region of TM7. The distance between TM3 and TM6 is subsequently increased, resulting in the opening of the intracellular binding pocket that enables G protein binding. Further analysis of the force distribution network in the receptor yielded a detailed molecular understanding of the signal transmission network that is activated upon agonist binding.

更新日期：2019-10-16

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