The multimerization pathway of the glucocorticoid receptor
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.
Authors
- Marta Vilaseca (ORCID: https://orcid.org/0000-0002-1666-1300)
- Alba Jiménez‐Panizo (ORCID: https://orcid.org/0000-0001-7046-6162)
- Maria Nuria Peralta-Moreno (ORCID: https://orcid.org/0000-0002-7762-0406)
- Juan Fernández‐Recio (ORCID: https://orcid.org/0000-0002-3986-7686)
- Gordon L. Hager (ORCID: https://orcid.org/0000-0002-9300-5331)
- Paloma Pérez (ORCID: https://orcid.org/0000-0002-7166-2824)
- Sohyoung Kim (ORCID: https://orcid.org/0000-0002-6140-7918)
- Mireia Díaz
- Andrea Alegre‐Martí (ORCID: https://orcid.org/0000-0001-6646-8798)
- Pablo Fuentes‐Prior (ORCID: https://orcid.org/0000-0002-6618-3204)
- Thomas A. Johnson (ORCID: https://orcid.org/0000-0002-9135-3252)
- Montserrat Abella (ORCID: https://orcid.org/0000-0002-5472-7788)
- Eva Estébanez‐Perpiñá (ORCID: https://orcid.org/0000-0003-2687-5801)
- Diego M. Presman (ORCID: https://orcid.org/0000-0003-4515-8058)
- Inés Montoya-Novoa (ORCID: https://orcid.org/0009-0005-1369-7382)
- J. Rubio (ORCID: https://orcid.org/0000-0002-5529-2325)
- Agustina L. Lafuente
- Pilar Montanyà-Valluguera
- Josep Ponsetí-Pons
Institutions
- National Institutes of Health (US)
- Institut Botànic de Barcelona (ES)
- Institute for Research in Biomedicine (ES)
- Barcelona Institute of Science and Technology (ES)
- National Cancer Institute (US)
- Instituto de Biomedicina de Valencia (ES)
- Gobierno de La Rioja (ES)
- Fundación Ciencias Exactas y Naturales (AR)
- Universitat de Barcelona (ES)
Publication Details
- Journal
- Nucleic Acids Research
- Published
- 2025-09-18
- DOI
- https://doi.org/10.1093/nar/gkaf1003
- Citations
- 1
- Primary Topic
- Estrogen and related hormone effects
- Type
- article
- Field-Weighted Citation Impact
- 1.82