Bruno Nelson E, Nwachukwu Jerome C, Srinivasan Sathish, Nettles Charles C, Izard Tina, Jin Zhuang, Nowak Jason, Cameron Michael D, Boregowda Siddaraju V, Phinney Donald G, Elemento Olivier, Liu Xu, Ortlund Eric A, Houtman René, Stavreva Diana A, Hager Gordon L, Kamenecka Theodore M, Kojetin Douglas J, Nettles Kendall W
Department of Integrative Structural and Computational Biology, The Scripps Research Institute, Jupiter, FL, USA.
Department of Molecular Medicine, The Scripps Research Institute, Jupiter, FL, USA.
Nat Chem Biol. 2021 Mar;17(3):307-316. doi: 10.1038/s41589-020-00719-w. Epub 2021 Jan 28.
Glucocorticoids display remarkable anti-inflammatory activity, but their use is limited by on-target adverse effects including insulin resistance and skeletal muscle atrophy. We used a chemical systems biology approach, ligand class analysis, to examine ligands designed to modulate glucocorticoid receptor activity through distinct structural mechanisms. These ligands displayed diverse activity profiles, providing the variance required to identify target genes and coregulator interactions that were highly predictive of their effects on myocyte glucose disposal and protein balance. Their anti-inflammatory effects were linked to glucose disposal but not muscle atrophy. This approach also predicted selective modulation in vivo, identifying compounds that were muscle-sparing or anabolic for protein balance and mitochondrial potential. Ligand class analysis defined the mechanistic links between the ligand-receptor interface and ligand-driven physiological outcomes, a general approach that can be applied to any ligand-regulated allosteric signaling system.
糖皮质激素具有显著的抗炎活性，但其使用受到包括胰岛素抵抗和骨骼肌萎缩在内的靶向不良反应的限制。我们采用化学系统生物学方法——配体类别分析，来研究旨在通过不同结构机制调节糖皮质激素受体活性的配体。这些配体表现出多样的活性谱，提供了识别对心肌细胞葡萄糖代谢和蛋白质平衡有高度预测作用的靶基因和共调节因子相互作用所需的差异。它们的抗炎作用与葡萄糖代谢有关，但与肌肉萎缩无关。这种方法还预测了体内的选择性调节，鉴定出对蛋白质平衡和线粒体电位具有肌肉保护或合成代谢作用的化合物。配体类别分析定义了配体-受体界面与配体驱动的生理结果之间的机制联系，这是一种可应用于任何配体调节的变构信号系统的通用方法。
