Duchenne muscular dystrophy is a genetic disorder that shows chronic and progressive damage to skeletal and cardiac muscle leading to premature death. Antiinflammatory corticosteroids targeting the glucocorticoid receptor (GR) are the current standard of care but drive adverse side effects such as deleterious bone loss. Through subtle modification to a steroidal backbone, a recently developed drug, vamorolone, appears to preserve beneficial efficacy but with significantly reduced side effects. We use combined structural, biophysical, and biochemical approaches to show that loss of a receptor-ligand hydrogen bond drives these remarkable therapeutic effects. Moreover, vamorolone uniformly weakens coactivator associations but not corepressor associations, implicating partial agonism as the main driver of its dissociative properties. Additionally, we identify a critical and evolutionarily conserved intramolecular network connecting the ligand to the coregulator binding surface. Interruption of this allosteric network by vamorolone selectively reduces GR-driven transactivation while leaving transrepression intact. Our results establish a mechanistic understanding of how vamorolone reduces side effects, guiding the future design of partial agonists as selective GR modulators with an improved therapeutic index.

杜兴氏肌营养不良症是一种遗传性疾病，表现出对骨骼肌和心肌的慢性和进行性损伤，导致过早死亡。靶向糖皮质激素受体（GR）的抗炎皮质类固醇是目前的治疗标准，但会带来不利的副作用，例如有害的骨质流失。通过对甾体骨架的微妙修饰，最近开发的药物vamorolone似乎保留了有益的功效，但副作用却大大减少了。我们使用组合的结构，生物物理和生化方法来证明受体配体氢键的丧失驱动了这些显着的治疗作用。此外，沃莫洛酮均匀地削弱了共激活剂的缔合，但不减弱共抑制因子的缔合，这意味着部分激动是其解离性质的主要驱动力。另外，我们确定了关键的和进化上保守的分子内网络连接配体到coregulator结合表面。沃莫洛酮对这种变构网络的干扰选择性地降低了GR驱动的反式激活，同时使反式阻遏保持完整。我们的结果建立了对Vamorolone如何减少副作用的机械理解，指导了部分激动剂作为具有改善的治疗指数的选择性GR调节剂的未来设计。