DNA Binding Site Sequence Directs Glucocorticoid Receptor Structure and Activity

By Sebastiaan H. Meijsing, M. Pufall, A. So, D. Bates, Lin Chen, Keith R. Yamamoto. Science, 2009

696 citations recorded by the source corpus.

Genes are not simply turned on or off, but instead their expression is fine-tuned to meet the needs of a cell. How genes are modulated so precisely is not well understood. The glucocorticoid receptor (GR) regulates target genes by associating with specific DNA binding sites, the sequences of which differ between genes. Traditionally, these binding sites have been viewed only as docking sites. Using structural, biochemical, and cell-based assays, we show that GR binding sequences, differing by as little as a single base pair, differentially affect GR conformation and regulatory activity. We therefore propose that DNA is a sequence-specific allosteric ligand of GR that tailors the activity of the receptor toward specific target genes.

Subfields: Genetics, Immunology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/b6b6202b77fd08fec8d6a2ee30a7a07ceb6919ec

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In Genetics

In Immunology

J. Cidlowski

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Citations in the corpus

Sequence and chromatin determinants of cell-type–specific transcription factor binding (2012, background): “Furthermore, different k-mer patterns not only may recruit different complexes but may actually allosterically alter the protein function (Meijsing et al. 2009).”
The Biology of the Glucocorticoid Receptor: New Signaling Mechanisms in Health and Disease (2013, background): “The specific cofactors assembled and their subsequent activity are dictated by both the nature of the glucocorticoid ligand and the specific GRE sequence bound by the receptor (37, 38).”
Origins of specificity in protein-DNA recognition (2010, positive): “Moreover, different GR-binding sites result in distinct GR activities, which, on the basis of X-ray data, could be explained by changes in the orientation of a GR loop induced by a modification of DNA backbone contacts (111).”
Dual role of FoxA1 in androgen receptor binding to chromatin, androgen signalling and prostate cancer (2011, background): “The DNA sequence in itself may act as an allosteric ligand for nuclear receptors, thereby affecting both receptor confirmation and regulatory activity (Meijsing et al, 2009).”
Glucocorticoid receptor signaling in health and disease (2013, background): “It is this variability in DNA sequence within the GRE that dictates the outcome of GR-transcriptional activity [22].”
The Human Transcription Factors. (2018, neutral): “Many TFs can recruit multiple cofactors that have opposite effects (Frietze and Farnham, 2011; Rosenfeld et al., 2006; Schmitges et al., 2016), dependent on the local sequence context and availability of cofactors (Meijsing et al., 2009; Wong andStruhl, 2011).”
Glucocorticoid Receptor Confers Resistance to Anti-Androgens by Bypassing Androgen Receptor Blockade (2013, neutral): “Others have reported evidence of allosteric regulation of hormone receptor complexes by specific DNA sequences independent of binding affinity (Meijsing et al., 2009), a phenomenon that may also be relevant here. after Glucocorticoid Treatment In Vitro enes in control (n = 10), 4 day (n = 8), and…”