The multivalency of the glucocorticoid receptor ligand-binding domain explains its manifold physiological activities

Estebanez-Perpina, E.; Jimenez-Panizo, A.; Alegre-Marti, A.; Fettweis, G.; Abella, M.; Anton, R.; Tettey, T.; Schiltz, L. R.; Johnson, T. A.; Nunez-Barrios, I.; Font-Diaz, J.; Caelles, C.; Valledor, A.; Perez, P.; Rojas, A. M.; Fernandez-Recio, J.; Presman, D.; Hager, G. L.; Fuentes-Prior, P.

doi:10.1101/2021.10.01.462734

bioRxiv · 10.1101/2021.10.01.462734

The multivalency of the glucocorticoid receptor ligand-binding domain explains its manifold physiological activities

Estebanez-Perpina, E.·Jimenez-Panizo, A.·Alegre-Marti, A.·Fettweis, G.·Abella, M.·Anton, R.·Tettey, T.·Schiltz, L. R.·Johnson, T. A.·Nunez-Barrios, I.·Font-Diaz, J.·Caelles, C.·Valledor, A.·Perez, P.·Rojas, A. M.·Fernandez-Recio, J.·Presman, D.·Hager, G. L.·Fuentes-Prior, P.

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Abstract

The glucocorticoid receptor (GR) is a ubiquitously expressed transcription factor that controls metabolic and homeostatic processes essential for life. Although numerous crystal structures of the GR ligand-binding domain (GR-LBD) have been reported, the functional oligomeric state of the full-length receptor, which is essential for its transcriptional activity, remains disputed. Here we present five new crystal structures of agonist-bound GR-LBD, along with a thorough analysis of previous structural work. Biologically relevant homodimers were identified by studying a battery of GR point mutants including crosslinking assays in solution and quantitative fluorescence microscopy in living cells. Our results highlight the relevance of non-canonical dimerization modes for GR, especially of contacts made by loop L1-3 residues such as Tyr545. Our work unveils likely pathophysiologically relevant quaternary assemblies of the nuclear receptor with important implications for glucocorticoid action and drug design.

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Estebanez-Perpina, E., Jimenez-Panizo, A., Alegre-Marti, A., Fettweis, G., Abella, M., Anton, R., Tettey, T., Schiltz, L. R., Johnson, T. A., Nunez-Barrios, I., Font-Diaz, J., Caelles, C., Valledor, A., Perez, P., Rojas, A. M., Fernandez-Recio, J., Presman, D., Hager, G. L., Fuentes-Prior, P.. 2021-10-03. The multivalency of the glucocorticoid receptor ligand-binding domain explains its manifold physiological activities. https://doi.org/10.1101/2021.10.01.462734

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