NUCLEAR RECEPTORS & NUCLEAR RECEPTOR LIGAND BINDING DOMAINS

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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.