| Acetylcholine binding protein from molluscs is a tool to study ligand binding to pentameric ligand-gated ion channels (LGICs), such as nicotinic acetylcholine receptors (nAChR), serotonin 5HT3 receptors, gamma-aminobutyric acid (GABAA and GABAC) and glycine receptors. These ion channels primarily modulate chemical synaptic transmission. Mutations in receptors lead to diseases such as congenital myasthenia gravis, epilepsy, startle syndrome and alcohol sensitivity (Vafa and Schofield, 1998). nAChRs mediate nicotine addiction in chronic tobacco users. These receptors are the targets for drugs such as nicotine, curare, barbiturates, benzodiazepines, and anti-emetics. We have shown that acetylcholine binding protein (AChBP) is a valuable model for ligand-binding in LGIC's. We identified the protein, the pharmacology and the crystal structure of AChBP, which is now the generally accepted prototype for the ligand binding domain. In this program we want to create chimaeric receptors to understand the physiology of the receptor and we plan to generate mutant AChBPs to reveal ligand specificity and selectivity determining factors. These newly created AChBP-based tools to study LGIC function will also be used for X-ray crystallography to generate information for drug-targeting studies. This project will refine and expand the possibilities to use AChBPs as a tool in drug discovery for a variety of different diseases. |
