A fundamental principle of biomedicine is that drugs bind to proteins to influence their output and, hence, cell physiology. The overall goal of our experiments is to understand the mechanisms by which ligands bind to neuromuscular acetylcholine receptors, and how this event influences the probability that these membrane proteins allow ions to cross the cell membrane. These receptors are molecular machines that reversibly couple the energy of ligand binding to that for the mechanical work of a global conformational change. Our objective is to reveal the moving parts of the binding site apparatus, and to measure the energy changes associated with each part. By doing so we will understand, design and control how this receptor responds to drugs. This knowledge can be applied to closely-related receptors that are common targets for drugs (both therapeutic and of abuse) and play roles in behavior and diseases of the nervous system.
The experiments will establish the fundamental principles for engineering drugs to bind to receptors and cause them to change their functional output. A model system will be used to make the measurements, and the knowledge gained will be applied to a broad class of receptors important in human health and disease.
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