We have solved several X-ray crystallographic structures of TR ligand-binding domains (LBDs), including the rat (r) TR alpha and the human (h) TR beta bound to diverse ligands. The TR-LBD folding, comprised mostly of alpha-helices, is likely to be general for the superfamily. The ligand, buried in the receptor, forms part of its hydrophobic core. Tight fitting of ligand into the receptor explains its high affinity for the TR, although the structure suggests that ligands with even higher affinities might be generated. The kinetics of 3,5,3'-triiodo-L-thyronine (T3) and 3,5,3',5'-tetraiodo-L-thyronine (T4) binding suggest that folding around the ligand, rather than receptor opening, is rate-limiting for high affinity binding. TR beta mutations in patients with resistance to T3 cluster around the ligand; these different locations could differentially affect on other receptor functions and explain the syndrome's clinical diversity. Guided by the structure, mutations have been placed on the TR surface to define interactions with other proteins. They suggest that a similar surface in the LBD is utilized for homo- or heterodimerization on direct repeats and inverted palindromes but not on palindromes. Coactivator proteins that mediate TR transcriptional activation bind to a small surface comprised of residues on four helices with a well-defined hydrophobic cleft, which may be a target for pharmaceuticals. The coactivator-binding surface appears to form upon ligand-binding by the folding of helix 12 into the scaffold formed by helices 3, 4 and 5. The analysis of most currently used antagonists suggest that although they probably fit into the ligand-binding pocket, they possess a group that may alter proper folding of the receptor, with disruption of the coactivator-binding surface (the 'extension model').