5VA7

Glucocorticoid Receptor DNA Binding Domain - IL11 AP-1 recognition element Complex

Summary for 5VA7

• Entry DOI: 10.2210/pdb5va7/pdb
• Related: 5VA0
• Descriptor: Glucocorticoid receptor, DNA (5'-D(*AP*GP*GP*GP*TP*GP*AP*GP*TP*CP*AP*GP*GP*AP*TP*G)-3'), DNA (5'-D(*CP*AP*TP*CP*CP*TP*GP*AP*CP*TP*CP*AP*CP*CP*CP*T)-3'), ... (5 entities in total)
• Functional Keywords: nuclear receptor, transcription factor, dna binding, development, protein-dna complex, transcription-dna complex, transcription/dna
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 4
• Total formula weight: 25753.60

Authors

Weikum, E.R.,Ortlund, E.A. (deposition date: 2017-03-24, release date: 2017-08-09, Last modification date: 2024-03-06)

Primary citation

Weikum, E.R.,de Vera, I.M.S.,Nwachukwu, J.C.,Hudson, W.H.,Nettles, K.W.,Kojetin, D.J.,Ortlund, E.A.
Tethering not required: the glucocorticoid receptor binds directly to activator protein-1 recognition motifs to repress inflammatory genes.
Nucleic Acids Res., 45:8596-8608, 2017

PubMed Abstract: The glucocorticoid receptor (GR) is a ligand-regulated transcription factor that controls the expression of extensive gene networks, driving both up- and down-regulation. GR utilizes multiple DNA-binding-dependent and -independent mechanisms to achieve context-specific transcriptional outcomes. The DNA-binding-independent mechanism involves tethering of GR to the pro-inflammatory transcription factor activator protein-1 (AP-1) through protein-protein interactions. This mechanism has served as the predominant model of GR-mediated transrepression of inflammatory genes. However, ChIP-seq data have consistently shown GR to occupy AP-1 response elements (TREs), even in the absence of AP-1. Therefore, the current model is insufficient to explain GR action at these sites. Here, we show that GR regulates a subset of inflammatory genes in a DNA-binding-dependent manner. Using structural biology and biochemical approaches, we show that GR binds directly to TREs via sequence-specific contacts to a GR-binding sequence (GBS) half-site found embedded within the TRE motif. Furthermore, we show that GR-mediated transrepression observed at TRE sites to be DNA-binding-dependent. This represents a paradigm shift in the field, showing that GR uses multiple mechanisms to suppress inflammatory gene expression. This work further expands our understanding of this complex multifaceted transcription factor.

PubMed: 28591827
DOI: 10.1093/nar/gkx509

Experimental method

X-RAY DIFFRACTION (2.153 Å)