NUCLEAR RECEPTORS & NUCLEAR RECEPTOR LIGAND BINDING DOMAINS

类固醇/甲状腺激素受体超家族是重要的 在高等真核生物中的信号转导介质。 这些可溶性 核受体作为转录介质被激活， 特定的小分子激素;激素配体的例子 包括雌激素、甲状腺激素、视黄酸和糖皮质激素。 在 一般来说，当受体构象发生显著变化时， 激素结合 与受体结合的合成拮抗剂， 阻断激素作用的化合物可用作药物或生物化学探针。 到 迄今为止，尚未开发出甲状腺的合成拮抗剂 受体的 我们感兴趣的是了解 激动剂和拮抗剂作用， 通过结合现代合成化学和 结构生物学 我们开发了一种组合固相 制备羟基芪类似物文库的策略 非甾体雌激素激动剂。 鉴定了一系列类似物 从文库中筛选出在细胞培养系统中显示激动剂活性的 和雌激素受体结合。 在另一个项目中，我们 利用蛋白质晶体学结果指导甲状腺的设计 受体拮抗剂 甲状腺受体的晶体结构 最近在Robert Fletterick的实验室里得到了解决， 结构显示了几种新的受体相互作用， 指导拮抗剂的设计。

The steroid/thyroid hormone receptor superfamily are important mediators of signal transduction in higher eukaryotes. These soluble nuclear receptors are activated as transcription mediators by binding to specific small molecule hormones; examples of hormone ligands include estrogen, thyroid, retinoic acid, and glucocorticoid. In general, a significant receptor conformational change is induced upon hormone binding. Synthetic antagonists that bind to the receptors and block hormone action are useful as drugs or biochemical probes. To date, no synthetic antagonists have been developed for the thyroid receptor. We are interested in understanding the structural basis of agonist and antagonist action for this family of receptors and are approaching the problem by combining modern synthetic chemistry with structural biology. We have developed a combinatorial solid-phase strategy for preparing a library of hydroxystilbene analogs as non-steroidal estrogen agonists. A series of analogs was identified from the library which show agonist activity in a cell culture system and estrogen receptor binding in vitro. In another project, we are using protein crystallography results to guide the design of thyroid receptor antagonist. The crystal structure of the thyroid receptor has recently been solved in Robert Fletterick's laboratory and the structure shows several novel hormone-receptor interactions that may guide the design of antagonists.