Abstract
The glucocorticoid receptor (GR) is a steroid hormone receptor of the nuclear receptor family that regulates gene expression in response to glucocorticoid hormone signaling. Interaction with specific GR DNA binding sequences causes conformational changes in the GR DNA binding domain (DBD) that result in recruitment of specific sets of co-regulators that determine transcriptional outcomes. We have solved the crystal structure of GR DBD in its DNA-free state, the first such crystal structure from any nuclear receptor. In contrast to previous NMR structures, this crystal structure reveals that free GR DBD adopts a conformation very similar to DNA-bound states. The lever arm region is the most variable element in the free GR DBD. Molecular dynamics of the free GR DBD as well as GR DBD bound to activating and repressive DNA elements confirm lever arm flexibility in all functional states. Cluster analysis of lever arm conformations during simulations shows that DNA binding and dimerization cause a reduction in the number of conformations sampled by the lever arm. These results reveal that DNA binding and dimerization drive conformational selection in the GR DBD lever arm region and show how DNA allosterically controls GR structure and dynamics.
Highlights
Glucocorticoids (GCs) are steroid hormones that are involved in various fundamental processes at the cellular and organismal level
The current structure suggests that the orientation of H3 relative to the core DNA binding domain (DBD) is not fixed in the absence of DNA and adopts its active conformation only upon glucocorticoid receptor (GR) binding to a recognition sequence
The structure contains eight independent molecules in the asymmetric unit and superposition of these molecules reveals that the free GR DBD is very similar to its DNA-bound form
Summary
Glucocorticoids (GCs) are steroid hormones that are involved in various fundamental processes at the cellular and organismal level. GRɣ, a GR isoform resulting from alternative splicing, differs from GRα only by a single arginine inserted into the lever arm This difference results in distinct DNA binding properties, protein interaction partners, differential regulation of specific target genes and distinct functional roles at cellular level[4,15,16,17]. Together these studies suggest that the lever arm region is a flexible element whose specific conformational and dynamical state in a particular GR-DNA complex is responsible for the selective recruitment of co-factors to specific genomic loci
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