2025/09/18 by Andrea Alegre‐Martí, Alba Jiménez‐Panizo, Agustina L. Lafuente +16 · 1 voice
Biochemistry, Genetics and Molecular Biology · Medicine · #Adrenal Hormones and Disorders #Estrogen and related hormone effects #Receptor Mechanisms and Signaling
paper · pdf · doi:10.1093/nar/gkaf1003
openalex publication_date 2025/09/18 · openalex created_date 2025/10/22 · openalex updated_date 2026/08/01
The glucocorticoid receptor (GR) is a leading drug target due to its antiinflammatory and immunosuppressive roles. The functional oligomeric conformation of full-length GR (FL-GR), which is key for its biological activity, remains disputed. Here we present a new crystal structure of agonist-bound GR ligand-binding domain (GR-LBD) comprising eight copies of a noncanonical dimer. We verified the biological relevance of this dimer for receptor multimerization in wild-type and selected FL-GR mutants using molecular dynamics and crosslinking-mass spectrometry together with fluorescence microscopy and transcriptomic analysis in living cells. Self-association of this GR-LBD basic dimer in two mutually exclusive assemblies reveals clues for FL-GR multimerization and activity in cells. We propose a model for the structure of multidomain GR based on our new data and suggest a detailed oligomerization pathway. This model reconciles all currently available structural and functional information and provides a more comprehensive understanding of the rare disorder, generalized glucocorticoid resistance.