SECOND BINDING SITE ON THE GLUCOCORTICOID RECEPTOR

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The Principal Investigator has evidence that the glucocorticoid receptor contains a second hormone binding site. Its existence has been demonstrated by measuring the effect of antagonist steroids on the rate of agonist dissociation from the glucocorticoid receptor. Recent preliminary evidence suggests that ketoconazole, a non-steroidal compound also interacts with this site and other new results suggest that this site may control transformation of agonist-receptor complexes. Because of the specificity of this site it is hypothesized that this "regulatory" site mediates antagonist action. The goal of these studies is to characterize more fully this second, nonglucocorticoid binding site on the glucocorticoid receptor. Eight Specific Aims have been formulated. 1. to document further the presence of this second site on each of the forms of the glucocorticoid receptor (transformed and untransformed). 2. its location along the glucocorticoid receptor will be investigated. 3. the chemical milieu and binding preference of this site will be detailed. 4. the interaction of non-steroidal compounds with this second site will be assessed in order to determine whether any possess unique affinity. 5. newer, more rapid techniques of receptor analysis (HPLC and vertical tube ultracentirfugation) will be applied to investigate the effect of antiglucocorticoids on receptor structure. 6. the effect of antiglucocorticoids on transformation will be quantitated. 7. a search will be made for similar binding sites on other steroid hormone receptors. 8. the biopotency of antiglucocorticoids will be assessed in the AcT-20 cell. The significance of this research lies in its potential for developing a reliable theory of antiglucocorticoid hormone action. This, in turn, will lead to more effective ways of identifying clinically significant agents. It is expected that these compounds will be important not only in treating states of glucocorticoid excess but also as immunoregulators that can be used in treating malignancies.