SECOND BINDING SITE ON THE GLUCOCORTICOID RECEPTOR

主要研究者有证据表明糖皮质激素受体 含有第二个激素结合位点。 它的存在 通过测量拮抗剂类固醇对 激动剂从糖皮质激素受体解离。 近期初步 有证据表明，酮康唑，一种非甾体化合物， 与该网站互动，其他新的结果表明，该网站可能 控制激动剂-受体复合物的转化。 因为 该位点的特异性，假设该“调节”位点 介导拮抗剂作用。 这些研究的目的是更全面地描述这第二个， 糖皮质激素受体上的非糖皮质激素结合位点。 八 制定了具体目标。 1.为了进一步证明 糖皮质激素受体每种形式上的第二个位点 （变形和未变形）。 2.它的位置沿着糖皮质激素 将对受体进行研究。 3.化学环境和结合 这个网站的偏好将被详细说明。 4.的相互作用 将评估第二个部位的非甾体化合物， 确定是否有独特的亲和力。 5.更新，更快 受体分析技术（HPLC和垂直管 超离心）将被应用于研究的影响， 抗糖皮质激素对受体结构的影响。 6.的影响 将定量抗糖皮质激素对转化的影响。 7.搜索 将用于其他类固醇激素受体上的类似结合位点。 8.将在AcT-20中评估抗糖皮质激素的生物效价 cell. 这项研究的意义在于它的潜力，发展一个 抗糖皮质激素作用的可靠理论。 反过来，这将 导致更有效的方法来识别临床上重要的代理商。 预计这些化合物不仅在治疗癌症方面是重要的， 糖皮质激素过量的状态，但也作为免疫调节剂， 用于治疗恶性肿瘤。

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.