The aryl hydrocarbon receptor (AhR) is an intracellular receptor protein that 
regulates gene transcription in response to both man-made and natural ligands. A 
modular transactivaton domain (TAD) has been mapped to the 304 C-terminal amino 
acids and consists of acidic, Q-rich, and P/S/T-rich subdomains. We have used 
steady-state intrinsic tryptophan fluorescence and circular dichroism 
spectroscopy to investigate the conformation of the acidic Q-rich region. The 
results reveal that this region of the protein is structurally flexible but 
adopts a more folded conformation in the presence of the natural osmolyte 
trimethylamine N-oxide (TMAO) and the solvent trifluoroethanol (TFE). In 
protein-protein interaction studies, the acidic Q-rich region bound to 
components of the general transcription machinery [TATA-binding protein (TBP), 
TAF4, and TAF6] as well as the coactivator proteins SRC-1a and TIF2. The binding 
site for TBP mapped to the acidic subdomain, while SRC-1a bound preferentially 
to the Q-rich sequence. Significantly, the binding of TBP was modulated by 
induced folding of the TAD with TMAO. The results indicate that the AhR TAD 
makes multiple interactions with the transcriptional machinery and protein 
conformation plays a critical role in receptor function. Taken together, these 
findings support a role for protein folding in AhR action and suggest possible 
mechanisms of receptor-dependent gene activation.