Chemical systems biology reveals mechanisms of glucocorticoid receptor signaling.

TitleChemical systems biology reveals mechanisms of glucocorticoid receptor signaling.
Publication TypeJournal Article
Year of Publication2021
AuthorsBruno NE, Nwachukwu JC, Srinivasan S, Nettles CC, Izard T, Jin Z, Nowak J, Cameron MD, Boregowda SV, Phinney DG, Elemento O, Liu X, Ortlund EA, Houtman R, Stavreva DA, Hager GL, Kamenecka TM, Kojetin DJ, Nettles KW
JournalNat Chem Biol
Date Published2021 03
KeywordsA549 Cells, Allosteric Regulation, Animals, Anti-Inflammatory Agents, Cell Line, Transformed, Gene Expression Regulation, Glucose, Glucose Transporter Type 4, Humans, Lipopolysaccharides, Male, Membrane Potential, Mitochondrial, Mice, Mice, Inbred C57BL, Mitochondria, Muscle Fibers, Skeletal, Muscular Atrophy, Myoblasts, Rats, Receptors, Glucocorticoid, Signal Transduction, Structure-Activity Relationship

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.

Alternate JournalNat Chem Biol
PubMed ID33510451
Grant ListR01 DK124870 / DK / NIDDK NIH HHS / United States