6w9m

Structure of the Ancestral Glucocorticoid Receptor 2 ligand binding domain in complex with vamorolone and SHP coregulator fragment

spinqualitylabelsall models 6w9m, resolution 1.59Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6w9m is a 2 chain structure with sequence from Homo sapiens and Synthetic construct. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.59Å Ligands: GOL, TUV Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function A0A1X8XLE9_9ZZZZ Publication Abstract from PubMed 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. Disruption of a key ligand-H-bond network drives dissociative properties in vamorolone for Duchenne muscular dystrophy treatment.,Liu X, Wang Y, Gutierrez JS, Damsker JM, Nagaraju K, Hoffman EP, Ortlund EA Proc Natl Acad Sci U S A. 2020 Sep 29;117(39):24285-24293. doi: , 10.1073/pnas.2006890117. Epub 2020 Sep 11. PMID:32917814 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Glucocorticoid receptor 3D structures

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