The proposed studies address the ligand binding and ligand induced conformational changes of thyroid hormone receptors (TRs). T3 binding to the TR ligand binding domain (LBD) induces conformational changes that influence the TR's DNA binding properties and binding of TR to co-activators and co-repressors. The goal is to elucidate details of the TR structure and the induced conformational changes which allow TR to function as a hormone responsive gene regulator. The investigator recently determined the crystal structure of the rat TR-alpha-LBD bound to the T3 analog Dimit. This revealed that the ligand is buried in the receptor's interior, contributing to formation of the TR's hydrophobic core, and implies the ligand induces major conformational changes in the TR. In the proposed studies, the investigator plans to determine the crystal structure of the rat TR-alpha-LBD and the human TR-beta-LBD bound to T3 and triac. The investigator also plans to determine the crystal structure of the unliganded LBD and of the full-length human TR-beta. Analysis of the results should provide a much greater understanding of the determinants of ligand binding, ligand induced conformational changes, TR agonist actions and interrelations between the LBD and the rest of the receptor. The results should be applicable to the function of ligands that act through the nuclear receptor superfamily in general.
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