PROBING RECEPTOR STRUCTURES WITH UNNATURAL AMINO ACIDS

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This project will provide fundamental information on the structure and function of several types of neuroreceptors and ion channels (receptors). These are the fundamental molecules of the brain an nervous system. They are athe crucial structures associated with many disease states and are the targets of many therapeutic approaches. The work will employ a new tool recently developed in these labs - the ability to incorporate unnatural amino acids at specific sites in th receptors and to express the proteins in intact cells. When coupled with modern electrophysiological methods, this allows study of structure and function with unprecedented precision. In particular, the first target system will be the nicotinic acetylcholine receptor. This is a prototype neuroreceptor and is representative of a broad class of important structures. The investigations will reveal the manner in which ligands (agonists and antagonists) interact with the receptor and produce the characteristic gating response. These studies will also lead to the development of geometrical information concerning the overall layout of the protein . When coupled with modern computer modeling techniques, this will produce viable, three-dimensional structures for this class of receptors. The second target system will be the voltage-gated potassium channels and related structures. Again, both information on channel function and precise geometrical models will be developed.