Molecular Origins for the Dominant Negative Function of Human Glucocorticoid Receptor Beta

ABSTRACT This study molecularly elucidates the basis for the dominant negative mechanism of the glucocorticoid receptor (GR) isoform hGRβ, whose overexpression is associated with human glucocorticoid resistance. Using a series of truncated hGRα mutants and sequential mutagenesis to generate a series of hGRα/β hybrids, we find that the absence of helix 12 is neither necessary nor sufficient for the GR dominant negative phenotype. Moreover, we have localized the dominant negative activity of hGRβ to two residues and found that nuclear localization, in addition to heterodimerization, is a critical feature of the dominant negative activity. Molecular modeling of wild-type and mutant hGRα and hGRβ provides structural insight and a potential physical explanation for the lack of hormone binding and the dominant negative actions of hGRβ.