| Structural highlights
9hdf is a 32 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Method: | X-ray diffraction, Resolution 2.78Å |
| Ligands: | , , , , , , , , , , |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Disease
NR0B2_HUMAN Defects in NR0B2 may be associated with obesity (OBESITY) [MIM:601665. It is a condition characterized by an increase of body weight beyond the limitation of skeletal and physical requirements, as the result of excessive accumulation of body fat.[1]
Function
NR0B2_HUMAN Acts as a transcriptional regulator. Acts as a negative regulator of receptor-dependent signaling pathways. Specifically inhibits transactivation of the nuclear receptor with whom it interacts. Inhibits transcriptional activity of NEUROD1 on E-box-containing promoter by interfering with the coactivation function of the p300/CBP-mediated trancription complex for NEUROD1.[2]
Publication Abstract from PubMed
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.
The multimerization pathway of the glucocorticoid receptor.,Alegre-Marti A, Jimenez-Panizo A, Lafuente AL, Johnson TA, Montoya-Novoa I, Peralta-Moreno MN, Montanya-Valluguera P, Ponseti-Pons J, Abella M, Kim S, Diaz M, Vilaseca M, Perez P, Fernandez-Recio J, Rubio-Martinez J, Presman DM, Hager GL, Fuentes-Prior P, Estebanez-Perpina E Nucleic Acids Res. 2025 Oct 14;53(19):gkaf1003. doi: 10.1093/nar/gkaf1003. PMID:41118578[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Nishigori H, Tomura H, Tonooka N, Kanamori M, Yamada S, Sho K, Inoue I, Kikuchi N, Onigata K, Kojima I, Kohama T, Yamagata K, Yang Q, Matsuzawa Y, Miki T, Seino S, Kim MY, Choi HS, Lee YK, Moore DD, Takeda J. Mutations in the small heterodimer partner gene are associated with mild obesity in Japanese subjects. Proc Natl Acad Sci U S A. 2001 Jan 16;98(2):575-80. Epub 2001 Jan 2. PMID:11136233 doi:10.1073/pnas.021544398
- ↑ Kim JY, Chu K, Kim HJ, Seong HA, Park KC, Sanyal S, Takeda J, Ha H, Shong M, Tsai MJ, Choi HS. Orphan nuclear receptor small heterodimer partner, a novel corepressor for a basic helix-loop-helix transcription factor BETA2/neuroD. Mol Endocrinol. 2004 Apr;18(4):776-90. Epub 2004 Jan 29. PMID:14752053 doi:10.1210/me.2003-0311
- ↑ Alegre-Martí A, Jiménez-Panizo A, Lafuente AL, Johnson TA, Montoya-Novoa I, Peralta-Moreno MN, Montanyà-Valluguera P, Ponsetí-Pons J, Abella M, Kim S, Díaz M, Vilaseca M, Pérez P, Fernández-Recio J, Rubio-Martínez J, Presman DM, Hager GL, Fuentes-Prior P, Estébanez-Perpiñá E. The multimerization pathway of the glucocorticoid receptor. Nucleic Acids Res. 2025 Oct 14;53(19):gkaf1003. PMID:41118578 doi:10.1093/nar/gkaf1003
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