Biological and Chemical Research Centre, Faculty of Chemistry, University of Warsaw, 02-093 Warsaw, Poland.
Department of Chemistry, Faculty of Sciences, Sorbonne Université, 75005 Paris, France.
Molecules. 2020 Apr 21;25(8):1930. doi: 10.3390/molecules25081930.
Most G protein-coupled receptors that bind the hydrophobic ligands (lipid receptors and steroid receptors) belong to the most populated class A (rhodopsin-like) of these receptors. Typical examples of lipid receptors are: rhodopsin, cannabinoid (CB), sphingosine-1-phosphate (S1P) and lysophosphatidic (LPA) receptors. The hydrophobic ligands access the receptor binding site from the lipid bilayer not only because of their low solubility in water but also because of a large N-terminal domain plug preventing access to the orthosteric binding site from the extracellular milieu. In order to identify the most probable ligand exit pathway from lipid receptors CB1, S1P1 and LPA1 orthosteric binding sites we performed at least three repeats of steered molecular dynamics simulations in which ligands were pulled in various directions. For specific ligands being agonists, the supervised molecular dynamics approach was used to simulate the ligand entry events to the inactive receptor structures. For all investigated receptors the ligand entry/exit pathway goes through the gate between transmembrane helices TM1 and TM7, however, in some cases it combined with a direction toward water milieu.
大多数与疏水性配体（脂类受体和甾体类受体）结合的 G 蛋白偶联受体都属于这些受体中分布最广的 A 类（视紫红质样）。脂类受体的典型例子有：视紫红质、大麻素（CB）、鞘氨醇-1-磷酸（S1P）和溶血磷脂酸（LPA）受体。疏水性配体不仅由于其在水中的低溶解度，而且由于大的 N 端结构域堵塞，阻止了配体从细胞外环境进入正位结合位点，从而进入受体结合位点。为了确定从 CB1、S1P1 和 LPA1 正位结合位点的脂类受体中最可能的配体出口途径，我们至少进行了三次导向分子动力学模拟，其中将配体沿不同方向拉动。对于特定的配体作为激动剂，使用有监督的分子动力学方法模拟配体进入非活性受体结构的事件。对于所有研究的受体，配体的进入/退出途径都通过跨膜螺旋 TM1 和 TM7 之间的门，但在某些情况下，它与朝向水介质的方向相结合。
