Protein activity can be allosterically regulated by the binding of ligands or cofactors outside the protein’s active site. The ability of nuclear hormone receptors to bind DNA and influence the transcription of target genes, for example, is affected by hormone binding. The transcriptional regulatory activity of these receptors is generally thought to be determined by the affinity with which they bind the DNA target. Meijsing et al., however, report that the transcriptional regulatory activity of the glucocorticoid receptor (GR) does not correlate with the affinity with which it binds to different GR binding sites (GBSs), but rather with the sequence of the GBS. Structural studies revealed that the conformation of the lever arm (the domain through which GR exerts its transcriptional regulatory activity) was determined by the sequence of the GBS to which GR was bound. The ability of specific DNA sequences to allosterically regulate the transcriptional regulatory activity of GR could thus provide a mechanism through which gene-specific regulatory activity might be achieved.
S. H. Meijsing, M. A. Pufall, A. Y. So, D. L. Bates, L. Chen, K. R. Yamamoto, DNA binding site sequence directs glucocorticoid receptor structure and activity. Science 324, 407–410 (2009). [Abstract] [Full Text]