National Academy of Sciences, Proceedings of the National Academy of Sciences, 39(117), p. 24285-24293, 2020
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Significance Corticosteroids that are currently in clinical use bind to the glucocorticoid receptor (GR) to exert antiinflammation effects, yet are associated with undesirable side effects. Vamorolone is a recently developed drug for Duchenne muscular dystrophy; it decreases muscle inflammation and reduces side effects observed in other corticosteroid-based treatments. Our structure studies reveal a crucial GR-ligand hydrogen bond is not possible in vamorolone. An unprecedented allosteric intramolecular network derived from this hydrogen bond modulates GR dynamic motions and coregulator binding. Our work provides insights into how subtle modifications on a drug exploits structural and dynamic properties in the receptor to dissociate downstream side effects from therapeutic benefits.