The primary goal of this project is to achieve a molecular level understanding of the biological and physiological events surrounding steroid synthesis, function and metabolism. A secondary goal is to use this knowledge to facilitate the development of safe, effective drugs for use as steroid agonists and antagonists in controlling fertility, in cancer chemotherapy, and in the treatment of steroid hormone related disorders and deficiencies. In order to obtain the detailed molecular images necessary for the realization of these goals, X-ray crystal structure determinations of hormonal steroids and the proteins with which they interact will be undertaken, and a continuing effort to discover correlations between molecular conformation and biological activity will be made. The proteins to be studied are representative of steroid binding and steroid metabolizing proteins. They include 3Alpha,20Beta-hydroxysteroid dehydrogenase from Streptomyces hydrogenans, 3Beta-hydroxysteroid specific alcohol dehydrogenase, rat liver 3Alpha-hydroxysteroid dehydrogenase, rat prostatic binding protein and guinea pig corticosteroid binding globulin. Maintenance of a complete data bank of all known steroid crystal structures through the NIH/PROPHET computer network will insure dissemination of structural information to the scientific community. As a result of our past efforts to correlate steroid structure with protein binding and hormone action, we have postulated that the A rings of estrogens, progestins, glucocorticoids, and mineralocorticoids play a dominant role in initiating receptor binding while the D rings have primary control over subsequent events associated with hormonal activity. This """"""""A-ring binding/D-ring acting"""""""" model provides a powerful tool for categorizing structural features and contributing to the development of clinically useful hormone agonists and antagonists. During the next five years we will test, extend and exploit the implications of this model.
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