5e6c
From Proteopedia
Glucocorticoid receptor DNA binding domain - CCL2 NF-kB response element complex
Structural highlights
Disease[GCR_HUMAN] Defects in NR3C1 are a cause of glucocorticoid resistance (GCRES) [MIM:138040]; also known as cortisol resistance. It is a hypertensive, hyperandrogenic disorder characterized by increased serum cortisol concentrations. Inheritance is autosomal dominant.[1] [2] [3] [4] [5] Function[GCR_HUMAN] Receptor for glucocorticoids (GC). Has a dual mode of action: as a transcription factor that binds to glucocorticoid response elements (GRE), both for nuclear and mitochondrial DNA, and as a modulator of other transcription factors. Affects inflammatory responses, cellular proliferation and differentiation in target tissues. Could act as a coactivator for STAT5-dependent transcription upon growth hormone (GH) stimulation and could reveal an essential role of hepatic GR in the control of body growth. Involved in chromatin remodeling. Plays a significant role in transactivation.[6] Publication Abstract from PubMedGlucocorticoids (GCs) are potent repressors of NF-kappaB activity, making them a preferred choice for treatment of inflammation-driven conditions. Despite the widespread use of GCs in the clinic, current models are inadequate to explain the role of the glucocorticoid receptor (GR) within this critical signaling pathway. GR binding directly to NF-kappaB itself-tethering in a DNA binding-independent manner-represents the standing model of how GCs inhibit NF-kappaB-driven transcription. We demonstrate that direct binding of GR to genomic NF-kappaB response elements (kappaBREs) mediates GR-driven repression of inflammatory gene expression. We report five crystal structures and solution NMR data of GR DBD-kappaBRE complexes, which reveal that GR recognizes a cryptic response element between the binding footprints of NF-kappaB subunits within kappaBREs. These cryptic sequences exhibit high sequence and functional conservation, suggesting that GR binding to kappaBREs is an evolutionarily conserved mechanism of controlling the inflammatory response. Cryptic glucocorticoid receptor-binding sites pervade genomic NF-kappaB response elements.,Hudson WH, Vera IMS, Nwachukwu JC, Weikum ER, Herbst AG, Yang Q, Bain DL, Nettles KW, Kojetin DJ, Ortlund EA Nat Commun. 2018 Apr 6;9(1):1337. doi: 10.1038/s41467-018-03780-1. PMID:29626214[7] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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