Figure 3: Simplified model illustrating the two major modes of NR activation. Natural or synthetic ligands diffuse through the cell membrane and bind to cytosolic or nuclear NRs. Ligand binding to cytoplasmic NRs triggers conformational changes resulting in dissociation of heat shock proteins (HSPs) and receptor dimerization, allowing active nuclear import and transactivation by binding to HREs. Other NRs are constitutively nuclear and complexed with corepressors in the absence of ligands. Ligand binding induces conformational changes resulting in the recruitment of coactivators to activate transcription of target genes.