Cell-cell communication and their functional coordination are a fundamental process of living organisms. Hormones, including small molecule neurotransmitters, peptides, and secreted proteins, are the most effective mediators of cell-to-cell signaling transduction.   Hormone recognition by their receptors is the first step of hormone-mediated signal transduction. Two major classes of hormone receptors are nuclear receptors and G protein coupled receptors (GPCRs), which are also two major classes of drug targets. For the past few decades, our laboratory has been focusing on the structure and function of hormone receptors as well as structured based drug discovery targeting these receptors. In this meeting, I will first present our works in the areas of nuclear receptors by revealing the overall helical sandwiched fold of the nuclear receptor ligand-binding domain (LBD) and the topology of ligand binding pocket. Using the glucocorticoid receptor (GR) as an example, I will display how the ligand binding pocket will changes its topology to accommodate its bound ligands, and how this information was used to design a new generation of glucocorticoid drug with reduced side effects. I will then move on to our works in the area of GPCRs, which functions are mediated primarily through two pathways: G protein and arrestin. Biased ligands that selectively activated either G protein or arrestin pathways often display better safety profile than the balanced ligand that activated both pathways, thus biased ligands have become a new paradigm of GPCR drug discovery. Over the past 15 years, our laboratory have solved the structures of the first GPCR-arrestin complex as well as the first set of structures of GPCR in complex with the inhibitory G protein Gi.
 

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