The objective of the proposed research is to establish structural reasons for the general hormonal activity of thyroactive compounds and for the explicit endocrine mechanisms which mediate metabolic processes. It has been shown that the activity of the thyroid hormones and their metabolites depends primarily on the structure and relative orientations of the various moieties in the molecule. Studies of biological activity and receptor binding affinity data indicate unique structural requirements for activity and suggest stringent conformational preferences for recognition by the receptor. Only with a more detailed understanding of the nature of these hormones at the molecular level, which can be obtained from X-ray crystallographic determinations of appropriately chosen hormone analogues, precursors, and metabolites, can a full understanding of their mechanism of action be obtained. Structural studies of the thyroid hormone precursors as well as the by-products of hormone coupling reactions will be studied to delineate the mechanism of thyroid hormone biosynthesis. These crystallographic studies will also unequivocally identify the stable conformational isomers of the thyroid hormones, delineate the differing degree of flexibility possessed by the various isomers, and define the nature of long-range interactions. These data are necessary for a full understanding of the basic mechanism of thyroid hormone activity and biosynthesis and are a key to interpretation of their biochemical and physiological action. In addition, crystallization experiments on the serum transport protein, thyroxine-binding globulin, have been initiated as the next phase to obtain direct information concerning hormone-protein interactions.
