Despite the proven health benefits of estrogen replacement therapy (ERT) in their postmenopausal years, only 30% of women in the United States are currently receiving ERT because of a clear association between excessive exposure to synthetic estrogens and the development of cancer in several tissues including endometrium, breast, kidney and liver. As a result, many women are seeking effective and natural, plant- derived (phyto) estrogen replacement alternatives in their diet that so that they may maintain the beneficial properties of estrogens without receiving the genotoxic effects. Two of the major sources of dietary phytoestrogens are soy and red clover, and to a lesser extent licorice and hops. Four of the major phytoestrogen compounds in soy and red clover are the isoflavones genistein, daidzen, biochanin-A and formononetin. Two recently identified phytoestrogen compounds in licorice and hops are glabridin and 8-prenylnaringenin. All six of these compounds have been shown via in-vivo and/or in-vitro bioassays to have either estrogenic or anti-estrogenic activity, or a mixture of both depending on what estrogen receptor (ER) isozyme, alpha or beta, is being targeted. A comparison of the x-ray structure of genistein complexed with ER-beta, the only phytoestrogen-ER structure solved to date, to those of estradiol (agonist) bound to ER-alpha and Raloxifene (antagonist) bound to ER- beta, reveals that the phytoestrogen genistein induces a novel conformation in ER. This conformation is neither that of a pure agonist nor or a pure antagonist but is proposed to be a conformation in between. This result invokes the hypothesis that each of the dietary phytoestrogens may induce unique conformations in both ER-alpha and ER-beta that may induce the type of transciptional activity that gives desired estrogenic or anti-estrogenic effects without inducing harmful transcription events i.e. tumor cell growth and/or proliferation. The specific aims of this proposal are therefore to i.) solve the high resolution x-ray structures of ER-alpha and ER-beta complexed with the six phytoestrogens listed above and to ii.) construct a quantitative structure- activity relationship (QSAR) that can be used to predict a priori the biological activity of newly identified phytoestrogen compounds and to II.)aid in the design of new compounds that can serve as selective estrogen modulators (SERMs).