The long range goal of this project is to investigate the mechanism of action of the peptide hormone glucagon and to contribute to the understanding of its role in the pathophysiology of diabetes mellitus. The principal approach towards this goal is to design and synthesize peptide analogs that will be potent antagonists of the hormone, using solid phase peptide synthesis. Such inhibitors are expected to provide insight into the structural basis of glucagon action at the molecular level, and might provide potentially therapeutic agents for the clinical management of hyperglycemia and ketoacidosis associated with diabetes. A second complementary approach is to investigate structure-function relationships in the glucagon receptor by site-directed mutagenesis and the biochemical and pharmacological characterization of mutant receptors. Specifically, the residues of the receptor that participate directly in glucagon recognition and mediate the subsequent transduction of the hormonal signal to intracellular effectors, will be identified. Information on the chemical features of the glucagon binding site is crucial for the conception of three-dimensional receptor models to be used in the rational design of glucagon antagonists of potential clinical value. To augment both approaches, glucagon interaction with its receptor will also be investigated using biophysical methods. Fluorescence and electron paramagnetic resonance spectroscopy will be used to monitor changes that accompany receptor activation. Nuclear magnetic resonance studies of glucagon bound to its receptor will be initiated. The combination of synthetic chemical approaches with molecular biology and biophysical methods is very likely to advance the understanding of glucagon-mediated signal transduction.
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