Chemical systems biology reveals mechanisms of glucocorticoid receptor signaling

• Published in: Nature chemical biology Vol. 17; no. 3; pp. 307 - 316
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: United States Nature Publishing Group 01.03.2021
• Subjects: A549 Cells; Allosteric properties; Allosteric Regulation; Animals; Anti-inflammatory agents; Anti-Inflammatory Agents - chemical synthesis; Anti-Inflammatory Agents - pharmacology; Atrophy; Biology; Cell Line, Transformed; Gene Expression Regulation; Glucocorticoids; Glucose; Glucose - metabolism; Glucose Transporter Type 4 - genetics; Glucose Transporter Type 4 - metabolism; Humans; Inflammation; Insulin; Insulin resistance; Ligands; Lipopolysaccharides - administration & dosage; Male; Membrane Potential, Mitochondrial - drug effects; Mice; Mice, Inbred C57BL; Mitochondria; Mitochondria - drug effects; Mitochondria - metabolism; Muscle Fibers, Skeletal - drug effects; Muscle Fibers, Skeletal - metabolism; Muscle Fibers, Skeletal - pathology; Muscles; Muscular Atrophy - chemically induced; Muscular Atrophy - drug therapy; Muscular Atrophy - genetics; Muscular Atrophy - metabolism; Myoblasts - drug effects; Myoblasts - metabolism; Myocytes; Proteins; Rats; Receptors; Receptors, Glucocorticoid - chemistry; Receptors, Glucocorticoid - genetics; Receptors, Glucocorticoid - metabolism; Side effects; Signal Transduction - drug effects; Signalling systems; Skeletal muscle; Structure-Activity Relationship; Target recognition; Transcription
• ISSN: 1552-4450; 1552-4469
• DOI: 10.1038/s41589-020-00719-w

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.