Dataset Information

The multimerization pathway of the glucocorticoid receptor

ABSTRACT: The glucocorticoid receptor (GR/NR3C1), a ligand-activated transcription factor belonging to the nuclear receptor (NR) superfamily, is vital for life. Like other NRs, GR features an intrinsically disordered N-terminal domain (NTD) followed by a highly conserved DNA-binding domain (DBD) and a hormone- or ligand-binding domain (LBD), separated by a long linker. While the receptor's quaternary structure is critical for its transcriptional activity, its precise multimeric organization has remained elusive. Here, we conducted a comprehensive crosslinking-mass spectrometry (XL-MS) analysis using cleavable crosslinkers (DSSO and DSBU) to investigate the quaternary structure of the GR DBD-linker-LBD tandem. Our results strongly support a model of non-canonical receptor multimerization, revealing that GR monomers arrange in a parallel fashion through interactions involving residues within the LBD's L1-3 loop (evidenced by XLs K576-K576’ and K579-K579’). These parallel, non-canonical dimers then further associate to form dimers-of-dimers, mediated by contacts within the H9/L9-10/H10 region (e.g., K695-K695’). This study provides unambiguous evidence for a novel GR multimerization mechanism and has important implications for the design of glucocorticoids with fewer side effects.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Marta Vilaseca

LAB HEAD: Marta Vilaseca

PROVIDER: PXD065782 | Pride | 2025-10-27

REPOSITORIES: Pride

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Dataset's files

Source:

			Action	DRS
	5073_IM.fasta	Fasta
	5073_IM_A1_A2_Tryp_S01.msf	Msf
	5073_IM_A1_A2_Tryp_S01.mzML	Mzml
	5073_IM_A3_A4_Tryp_S02.msf	Msf
	5073_IM_A3_A4_Tryp_S02.mzML	Mzml

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The multimerization pathway of the glucocorticoid receptor.

Alegre-Martí Andrea A Jiménez-Panizo Alba A Lafuente Agustina L AL Johnson Thomas A TA Montoya-Novoa Inés I Peralta-Moreno M Nuria MN Montanyà-Valluguera Pilar P Ponsetí-Pons Josep J Abella Montserrat M Kim Sohyoung S Díaz Mireia M Vilaseca Marta M Pérez Paloma P Fernández-Recio Juan J Rubio-Martínez Jaime J Presman Diego M DM Hager Gordon L GL Fuentes-Prior Pablo P Estébanez-Perpiñá Eva E

Nucleic acids research 20251001 19

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 ...[more]

PMID: 41118578

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