Laboratory of Chemical Biology, Department of Biomedical Engineering and Institute for Complex Molecular Systems (ICMS), Eindhoven University of Technology, Eindhoven, The Netherlands.
Laboratory of Chemical Biology, Department of Biomedical Engineering and Institute for Complex Molecular Systems (ICMS), Eindhoven University of Technology, Eindhoven, The Netherlands.
Bioorg Med Chem. 2022 Aug 15;68:116877. doi: 10.1016/j.bmc.2022.116877. Epub 2022 Jun 10.
The nuclear receptor peroxisome proliferator-activated receptor gamma (PPARγ) plays a central role in metabolic processes. PPARγ full agonists have side effects, arguing for the discovery of PPARγ partial agonists with novel chemotypes. We report the unique binding mode of the known allosteric retinoic acid receptor-related orphan receptor gamma t (RORγt) ligand MRL-871 to PPARγ. MRL-871 binds between PPARγ helices 3, 5, 7 and 11, where it stabilizes the beta-sheet region with a hydrogen bond between its carboxylic acid moiety and PPARγ Ser370. Its unique binding mode differs from that of the benzoyl 2-methyl indoles which are well-studied, structurally similar, PPARγ ligands. MRL-871's high affinity for PPARγ induces only limited coactivator stabilization, highlighting its attractive partial agonistic characteristics. Affinity comparison of MRL-871 and related compounds towards both RORγt and PPARγ indicates the possibility for tuning of selectivity, bringing MRL-871 forward as an interesting starting point for novel PPARγ ligands.
核受体过氧化物酶体增殖物激活受体 γ (PPARγ) 在代谢过程中起着核心作用。PPARγ 全激动剂有副作用，因此需要发现具有新型化学结构的 PPARγ 部分激动剂。我们报告了已知的变构维甲酸受体相关孤儿受体 γ t (RORγt) 配体 MRL-871 与 PPARγ 的独特结合模式。MRL-871 结合在 PPARγ 的螺旋 3、5、7 和 11 之间，在那里它通过其羧酸部分和 PPARγ Ser370 之间的氢键稳定β-折叠区域。它独特的结合模式与结构相似的苯甲酰 2-甲基吲哚类，即研究得很好的 PPARγ 配体不同。MRL-871 对 PPARγ 的高亲和力仅诱导有限的共激活剂稳定化，突出了其有吸引力的部分激动特性。MRL-871 及其相关化合物对 RORγt 和 PPARγ 的亲和力比较表明，选择性调整的可能性，使 MRL-871 成为新型 PPARγ 配体的一个有趣起点。
