Agonism activities of lyso-phosphatidylcholines (LPC) Ligands binding to peroxisome proliferator-activated receptor gamma (PPARgamma).
Agonism activities of lyso-phosphatidylcholines (LPC) Ligands binding to peroxisome proliferator-activated receptor gamma (PPARgamma).
复制标题
溶血磷脂酰胆碱 (LPC) 配体与过氧化物酶体增殖物激活受体 γ (PPARgamma) 结合的激动活性。
DOI：
10.1080/07391102.2019.1577175
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发表时间：
2019
影响因子：
4.4
通讯作者：
Zhang Yan
中科院分区：
文献类型：
--
作者：
Wang Jiayue;Wang Bohong;Zhang Yan
过氧化物酶体增殖物激活受体（peroxisome proliferator-activated receptor，PPAR γ）属于核受体超家族，是治疗2型糖尿病药物的主要靶点。实验发现溶血磷脂酰胆碱（LPC）能与PPARγ结合，但结合方式尚不清楚。我们采用分子对接和分子动力学（MD）模拟方法研究了四种LPC配体（LPC 16：0、LPC 18：0、LPC 18：1-1和LPC 18：1-2）与PPARγ的结合。采用两步MD模拟来确定最终结合模式。对4个最终LPC-PPARγ复合物进行20 ns MD模拟，以分析其结构、结合关键残基和激动活性。结果表明，三种LPC配体（LPC 16：0、LPC 18：0和LPC 18：1-1）与配体结合结构域（LBD）口袋的Arm II和III区域结合，而它们不与Helix 12（H12）的Tyr 473相互作用。相反，LPC 18：1-2可以与Tyr 473形成氢键并结合到臂I和II区域中。结果表明，LPC 16：0、LPC 18：0和LPC 18：1-1可能是潜在的部分激动剂，LPC 18：1-2可能是完全激动剂。残基波动和结构比对的深入分析证实了LPC激动活性的当前预测。
PPARγ is an isoform of peroxisome proliferator-activated receptor (PPAR) belonging to a super family of nuclear receptors and is a primary target of the effective drug to treat the type II diabetes. The experiments found that Lyso-phosphatidylcholines (LPC) could bind to PPARγ, but the binding modes remain unknown. We used the Molecular Docking and Molecular Dynamic (MD) simulations to study the binding of four LPC ligands (LPC16: 0, LPC18: 0, LPC18: 1-1 and LPC18: 1-2) to PPARγ. The two-step MD simulations were employed to determine the final binding modes. The 20 ns MD simulations for four final LPC-PPARγ complexes were performed to analyze their structures, the binding key residues, and agonism activities. The results reveal that three LPC ligands (LPC16: 0, LPC18: 0 and LPC18: 1-1) bind to Arm II and III regions of the Ligand Binding Domain (LBD) pocket, whereas they do not interact with Tyr473 of Helix 12 (H12). In contrast, LPC18: 1-2 can form the hydrogen bonds with Tyr473 and bind into Arm I and II regions. Comparing with the paradigm systems of the full agonist (Rosiglitazone–PPARγ) and the partial agonist (MRL24–PPARγ), our results indicate that LPC16: 0, LPC18: 0 and LPC18: 1-1 could be the potential partial agonists and LPC18: 1-2 could be a full agonist. The in-depth analysis of the residue fluctuations and structure alignment confirm the present prediction of the LPC agonism activities.