Abstract
CELL BIOLOGY The transcriptional activity of a nuclear receptor depends not only on its dimerization with another nuclear receptor but also on the functional communication between four distinct domains within its ligand-binding domain (LBD). For example, the retinoid X receptor (RXR) heterodimer is differentially responsive to ligands through allosteric communication within the LBDs and across the dimerization interface. However, it is not clear how ligand binding propagates through the LBD to affect the sites that mediate cofactor, coregulator, and DNA binding; receptor dimerization; and transcription. Shulman et al. analyzed the LBD sequences of 250 nuclear receptors and identified a network of 27 residues that mediate allosteric communication. Certain residue pairs were energetically coupled and thus likely to have coevolved to maintain a specific function—global interaction between these pairs predicted the allosteric network. Nettles et al. examined allostery in estrogen receptor subtypes that underlies their differential responses to ligands. Residues outside the ligand-binding pocket contributed to the subtype-specific positioning of bound ligands. The coactivator-binding pocket also affected ligand positioning through the conformation of a specific helix, suggesting that functional communication between these two regions of the LBD is bidirectional. — LDC Cell 116 , 417 (2004); Mol. Cell 13 , 317 (2004).
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