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Please use this identifier to cite or link to this item: https://hdl.handle.net/2445/228184
The multimerization pathway of the glucocorticoid receptor
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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.
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The multimerization pathway of the glucocorticoid receptor. Nucleic Acids Research. 2025. Vol. 53, num. 19, pags. 1-24. ISSN 0305-1048. [consulted: 13 of June of 2026]. Available at: https://hdl.handle.net/2445/228184