Nuclear receptor genes comprise a large family and encode receptors for thyroid and steroid hormones, vitamin D, retinoids, prostaglandins, and other ligands. These receptors regulate most human processes and are important pharmaceutical targets. The receptors contain amino-terminal, DNA-binding and ligand-binding (LBD) domains. Ligand-induced receptor conformational changes induce receptor activities that regulate transcription. Receptors mediate effects through interactions with other proteins, including coactivators and heterodimerizing partners. Central to understanding receptor actions is knowing their atomic structures. The Principal Investigator and colleagues first solved the X-ray structure of a liganded nuclear receptor LBD, that of the thyroid hormone receptor- alpha (TRalpha) that revealed insights into receptor function, and subsequently solved other structures, including TRalpha LBD bound to several ligands, human (h) TRbeta bound to agonists, including one that is TRbeta-selective, hTRbeta bound to a coactivator peptide and mutated hTRbeta forms that cause thyroid hormone resistance. These structures have revealed more information about receptor function, have been useful for designing a ligand that selectively modulates hTRbeta bound to a coactivator peptide and mutated hTRbeta forms that cause thyroid hormone resistance. These structures have revealed more information about receptor function, have been useful for designing a ligand that selectively modulates hTRbeta thyroid hormone response sand may be a prototype drug for treating obesity and hypercholesterolemia, and for designing thyroid hormone antagonists that may be prototypes for treating hyperthyroidism. In the proposed studies it is planned to determine the X-ray crystal structure of the hTRbeta PBD bound to several different ligands that perturb the structure in different ways, hTRbeta complexed with a retinoid X-receptor (RXR) heterodimerizing partner, and liganded hTRbeta LBD complexed with a novel coactivator peptide and a cyclized high affinity binding coactivator peptide. It is also planned to determine X-ray structures of RXR and TR DBD-LBD proteins and the full-length TR. The new structures should provide information about hormone-induced conformational changes, mechanisms of receptor interaction with other protein, the multiple receptor domains, and relations between domains. The results should yield insights into TR function and how ligands act as agonists or antagonist, are applicable to nuclear receptors in general, and may facilitate pharmaceutical design.